AU2014296107B2 - Growth differentiation factor 15 (GDF-15) constructs - Google Patents

Abstract

Constructs comprising GDF15, and mutants thereof are provided. In various embodiments the constructs comprising GDF15, and mutants thereof, can be of use in the treatment or ameliorating a metabolic disorder. In various embodiments the metabolic disease or disorder is type 2 diabetes, obesity, dyslipidemia, elevated glucose levels, elevated insulin levels and diabetic nephropathy.

Description

FIELD OF THE INVENTION

The instant disclosure relates to monomers and multimers comprising a polypeptide comprising a GDF15 region.

BACKGROUND OF THE INVENTION

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Growth differentiation factor 15 (GDF15) is a divergent member of the TGfp superfamily. It is also called macrophage inhibitory cytokine 1 (MIC1) (Bootcov MR, 1997, Proc Natl Acad Sci 94:11514-9), placental bone morphogenetic factor (PLAB) (Hromas R 1997, Biochim Biophys Acta. 1354:40-4), placental transforming growth factor beta (PTGFB) (Lawton LN 1997, Gene. 203:17-26), prostate derived factor (PDF) (Paralkar VM 1998, J

Biol Chem. 273:13760-7), and nonsteroidal anti-inflammatory drug-activated gene (NAG-1) (Baek SJ 2001, J Biol Chem. XC. 33384-92).

Human GDF 15 gene is located on chromosome 19p 13.2-13.1; rat GDF 15 gene is located on chromosome 16; and mouse GDF15 gene is located on chromosome 8. The GDF15 open reading frames span two exons (Bottner M 1999, Gene. 237:105-11 and NCBI).

The mature GDF 15 peptide shares low homology with other family members (Katoh M 2006, IntJMolMed. 17:951-5.).

GDF 15 is synthesized as a large precursor protein that is cleaved at the dibasic cleavage site to release the carboxyterminal mature peptide. The mouse and rat GDF 15 prepro-peptides both contain 303 amino acids. Human full-length precursor contains 308 amino acids. The rodent mature peptides contain 115 amino acids after processing at the RGRR (SEQ ID NO:1) cleavage site. The human mature peptide contains 112 amino acids after processing at the RGRRRAR (SEQ ID NO:2) cleavage site. Human mature GDF15 peptide shares 66.1% and 68.1% sequence similarity with rat and mouse mature GDF15 peptides (Bottner M 1999, Gene. 237:105-11; Bauskin AR 2000, EMBO J. 19:2212-20;

NCBI). There is no glycosylation site in the mature GDF15 peptide.

The mature GDF15 peptide contains the seven conserved cysteine residues required for the formation of the cysteine knot motif (having three intrachain disulfide bonds) and the single interchain disulfide bond that are typical for TGf β superfamily members. The mature

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GDF15 peptide further contains two additional cysteine residues that form a fourth intrachain disulfide bond. Biologically active GDF15 is a 25KD homodimer of the mature peptide covalently linked by one interchain disulfide bond.

GDF15 circulating levels have been reported to be elevated in multiple pathological 5 and physiological conditions, most notably pregnancy (Moore AG 2000. J Clin Endocrinol Metab 85: 4781-4788), β-thalassemia (Tanno T 2007, Nat Med 13:1096-101; Zimmermann MB, 2008 Am J Clin Nutr 88:1026-31), and congenital dyserythropoietic anemia (Tamary H 2008, Blood. 112:5241-4). GDF15 has also been linked to multiple biological activities in literature reports. Studies of GDF 15 knockout and transgenic mice suggested that GDF 15 may be protective against ischemic/reperfusion- or overload-induced heart injury (Kempf T, 2006, Circ Res.98:351-60; Xu J, 2006, Circ Res. 98:342-50), protective against agingassociated motor neuron and sensory neuron loss (Strelau J, 2009, J Neurosci. 29 :13640-8), mildly protective against metabolic acidosis in kidney, and may cause cachexia in cancer patients (Johnen H 2007 Nat Med. 11:1333-40). Many groups also have studied the role of

GDF 15 in cell apoptosis and proliferation and reported controversial results using different cell culture and xenograft models. Studies on transgenic mice showed that GDF 15 is protective against carcinogen or Ape mutation induced neoplasia in intestine and lung (Baek SJ 2006, Gastroenterology. 131:1553-60; CekanovaM 2009, Cancer Prev Res 2:450-8).

SUMMARY OF THE INVENTION

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

Provided herein are fusion proteins comprising a GDF 15 polypeptide or a GDF 15 mutant polypeptide and an Fc domain.

In a one embodiment, the Fc domain comprises a sequence selected from the group consisting of SEQ ID NOs: 16, 22, 28, 29, 33,35,38, 48, 85,91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302. In another embodiment, the GDF 15 polypeptide or a GDF 15 mutant polypeptide comprises a sequence selected from the group consisting of SEQ ID NOs:4, 8, 12, 25, 52 and 55. In another embodiment, the fusion protein further comprises a polypeptide linker. In one embodiment, the polypeptide linker has a sequence selected from the group consisting of SEQ ID NOs: 18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, 128. In one embodiment, the fusion protein comprises two or more Fc domains. In one embodiment, the fusion protein comprises two or more polypeptide linkers. In one embodiment, the fusion protein comprises

2014296107 16 May 2017 a sequence selected from the group consisting of SEQ ID NOs: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71, 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160, 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

2a

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Also provided herein are dimers comprising (i) a first polypeptide chain comprising one of the foregoing fusion proteins, and (ii) a second polypeptide chain comprising an Fc domain. In yet a further embodiment, the construct further comprises a sequence selected from the group consisting of SEQ ID NOs: 16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132,

141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282,

283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

In one embodiment, the first and second polypeptide chains are non-covalently associated. In another embodiment, the first and second polypeptide chains are covalently associated. In one embodiment, the first and second polypeptide chains are covalently associated via disulfide bonds between their respective Fc domains. In another embodiment, the first and second polypeptide chains are associated by both covalent and non-covalent interactions.

In a particular embodiment, a dimer is provided comprising: (a) two fusion proteins comprising the sequence of SEQ ID NO:46; (b) two fusion proteins comprising the sequence of SEQ ID NO:24; or (c) two fusion proteins comprising the sequence of SEQ ID NO:27

In a particular embodiment, a dimer is provided comprising (a) two fusion proteins comprising the sequence of SEQ ID NO:32; or (b) two fusion proteins comprising the sequence of SEQ ID NO:37;

In a particular embodiment, a dimer is provided comprising a first polypeptide chain comprising the sequence of SEQ ID NO:20 and a second polypeptide chain comprising the sequence of SEQ ID NO: 17.

In a particular embodiment, a dimer is provided comprising (a) a first polypeptide chain comprising the sequence of SEQ ID NO:42 and a second polypeptide chain comprising the sequence of SEQ ID NO:39; (b) a first polypeptide chain comprising the sequence of SEQ ID NO:50 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (c) a first polypeptide chain comprising the sequence of SEQ ID NO:54 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (d) a first polypeptide chain comprising the sequence of SEQ ID NO:57 and a second polypeptide chain comprising the sequence of SEQ

ID NO:47; (e) a first polypeptide chain comprising the sequence of SEQ ID NO:60 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (f) a first polypeptide chain comprising the sequence of SEQ ID NO:63 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (g) a first polypeptide chain comprising the sequence of SEQ ID NO:66 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (h) a first polypeptide chain comprising the sequence of SEQ ID NO:68 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (i) a first polypeptide chain comprising the sequence of SEQ ID NO:71 and a second polypeptide chain comprising the sequence of SEQ

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ID NO:47; (j) a first polypeptide chain comprising the sequence of SEQ ID NO:74 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (k) a first polypeptide chain comprising the sequence of SEQ ID NO:77 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (1) a first polypeptide chain comprising the sequence of SEQ

ID NO:80 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; (m) a first polypeptide chain comprising the sequence of SEQ ID NO:82 and a second polypeptide chain comprising the sequence of SEQ ID NO:47; or (n) a first polypeptide chain comprising the sequence of SEQ ID NO:84 and a second polypeptide chain comprising the sequence of SEQ ID NO:47.

In a particular embodiment, a dimer is provided comprising (a) a first polypeptide chain comprising the sequence of SEQ ID NO:88 and a second polypeptide chain comprising the sequence of SEQ ID NO:86; (b) a first polypeptide chain comprising the sequence of SEQ ID NO:93 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; (c) a first polypeptide chain comprising the sequence of SEQ ID NO:96 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; (d) a first polypeptide chain comprising the sequence of SEQ ID NO:98 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; (e) a first polypeptide chain comprising the sequence of SEQ ID NO: 100 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; (f) a first polypeptide chain comprising the sequence of SEQ ID NO: 102 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; (g) a first polypeptide chain comprising the sequence of SEQ ID NO: 104 and a second polypeptide chain comprising the sequence of SEQ ID NO:90; or (h) a first polypeptide chain comprising the sequence of SEQ ID NO: 108 and a second polypeptide chain comprising the sequence of SEQ ID NO: 105.

In a particular embodiment, a dimer is provided comprising (a) a first polypeptide chain comprising the sequence of SEQ ID NO:112 and a second polypeptide chain comprising the sequence of SEQ ID NO: 12; (b) two polypeptide chains, each comprising the sequence of SEQ ID NO: 112; (c) two polypeptide chains, each comprising the sequence of SEQ ID NO: 115; (d) two polypeptide chains, each comprising the sequence of SEQ ID NO:118; (e) two polypeptide chains, each comprising the sequence of SEQ ID NO:121; (f) two polypeptide chains, each comprising the sequence of SEQ ID NO: 124; (g) two polypeptide chains, each comprising the sequence of SEQ ID NO: 127; (h) two polypeptide chains, each comprising the sequence of SEQ ID NO: 130; or (i) two polypeptide chains, each comprising the sequence of SEQ ID NO:242.

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO: 134 and a second polypeptide chain comprising the sequence of SEQ ID NO:131; (b) a first polypeptide chain comprising the sequence of SEQ ID NO: 137 and a second polypeptide chain comprising the sequence of

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SEQ ID NO: 131; (c) a first polypeptide chain comprising the sequence of SEQ ID NO: 139 and a second polypeptide chain comprising the sequence of SEQ ID NO: 131; (d) a first polypeptide chain comprising the sequence of SEQ ID NO: 143 and a second polypeptide chain comprising the sequence of SEQ ID NO: 140; (e) a first polypeptide chain comprising the sequence of SEQ ID NO: 146 and a second polypeptide chain comprising the sequence of SEQ ID NO:140; (f) a first polypeptide chain comprising the sequence of SEQ ID NO:150 and a second polypeptide chain comprising the sequence of SEQ ID NO: 147; (g) a first polypeptide chain comprising the sequence of SEQ ID NO: 153 and a second polypeptide chain comprising the sequence of SEQ ID NO: 147; (h) a first polypeptide chain comprising the sequence of SEQ ID NO:269 and a second polypeptide chain comprising the sequence of SEQ ID NO:267; (i) a first polypeptide chain comprising the sequence of SEQ ID NO:272 and a second polypeptide chain comprising the sequence of SEQ ID NO:267; (j) a first polypeptide chain comprising the sequence of SEQ ID NO:276 and a second polypeptide chain comprising the sequence of SEQ ID NO:274; or (k) a first polypeptide chain comprising the sequence of SEQ ID NO:279 and a second polypeptide chain comprising the sequence of SEQ ID NO:274.

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO: 157 and a second polypeptide chain comprising the sequence of SEQ ID NO: 154; (b) a first polypeptide chain comprising the sequence of SEQ ID NO: 160 and a second polypeptide chain comprising the sequence of SEQ ID NO: 154; (c) a first polypeptide chain comprising the sequence of SEQ ID NO: 164 and a second polypeptide chain comprising the sequence of SEQ ID NO: 161; (d) a first polypeptide chain comprising the sequence of SEQ ID NO: 167 and a second polypeptide chain comprising the sequence of SEQ ID NO: 161.

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO: 171 and a second polypeptide chain comprising the sequence of SEQ ID NO: 168; or (b) a first polypeptide chain comprising the sequence of SEQ ID NO: 174 and a second polypeptide chain comprising the sequence of SEQ ID NO: 168

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO: 178 and a second polypeptide chain comprising the sequence of SEQ ID NO: 175; (b) a first polypeptide chain comprising the sequence of SEQ ID NO: 181 and a second polypeptide chain comprising the sequence of SEQ ID NO:175; (c) a first polypeptide chain comprising the sequence of SEQ ID NO:185 and a second polypeptide chain comprising the sequence of SEQ ID NO: 182; (d) a first polypeptide chain comprising the sequence of SEQ ID NO: 188 and a second polypeptide chain comprising the sequence of SEQ ID NO: 182; (e) a first polypeptide chain comprising

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PCT/US2014/049254 the sequence of SEQ ID NO: 194 and a second polypeptide chain comprising the sequence of SEQ ID NO:191; (f) a first polypeptide chain comprising the sequence of SEQ ID NO:197 and a second polypeptide chain comprising the sequence of SEQ ID NO: 191; (g) a first polypeptide chain comprising the sequence of SEQ ID NO:201 and a second polypeptide chain comprising the sequence of SEQ ID NO: 198; or (h) a first polypeptide chain comprising the sequence of SEQ ID NO:204 and a second polypeptide chain comprising the sequence of SEQ ID NO: 198.

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO:208 and a second polypeptide chain comprising the sequence of SEQ ID NO:205; (b) a first polypeptide chain comprising the sequence of SEQ ID NO:211 and a second polypeptide chain comprising the sequence of SEQ ID NO:205; (c) a first polypeptide chain comprising the sequence of SEQ ID NO:215 and a second polypeptide chain comprising the sequence of SEQ ID NO:212; or (d) a first polypeptide chain comprising the sequence of SEQ ID NO:218 and a second polypeptide chain comprising the sequence of SEQ ID NO:212.

In a particular embodiment, a dimer is provided comprising: (a) a first polypeptide chain comprising the sequence of SEQ ID NO:222 and a second polypeptide chain comprising the sequence of SEQ ID NO:219; (b) a first polypeptide chain comprising the sequence of SEQ ID NO:225 and a second polypeptide chain comprising the sequence of

SEQ ID NO:219; (c) a first polypeptide chain comprising the sequence of SEQ ID NO:229 and a second polypeptide chain comprising the sequence of SEQ ID NO:226; or (d) a first polypeptide chain comprising the sequence of SEQ ID NO:232 and a second polypeptide chain comprising the sequence of SEQ ID NO:226.

In a particular embodiment, a dimer is provided comprising: (a) two polypeptide chains, each comprising the sequence of SEQ ID NO:235; (b) two polypeptide chains, each comprising the sequence of SEQ ID NO:238; or (c) two polypeptide chains, each comprising the sequence of SEQ ID NO:240.

In certain embodiments, a tetramer is provided, comprising (i) a first dimer comprising one of the foregoing dimers and (ii) a second dimer comprising one of the foregoing dimers. In certain embodiments, the first polypeptide chain of the first dimer is linked to the first polypeptide chain of the second dimer via an interchain disulfide bond between their respective GDF15 regions.

In some embodiments, the dimer is not selected from the group comprising DhCpmF c(-)-(G₄S)4-GDF 15 :DhCpmF c(+)., DhCpmF c(+)-(G₄S)4-GDF 15 :DhCpmF c(-),

DhCpmFc(-)-(G₄S)₄-GDF15(H6D):DhCpmFc(+), DhCpmFc(+)-(G₄S)₄GDF15 (H6D) :DhCpmFc(-), DhCpmFc(+)-(G₄S)₄-GDF 15 (N3Q):DhCpmFc(-), DhCpmFc(+)GDF15 :DhCpmF c(-), DhCpmFc(+)-G₄-GDF 15 :DhCpmF c(-), DhCpmF c(+)-(G₄S)₂6

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GDF15 :DhCpmFc(-), DhCpmFc(+)-(G₄Q)₄-GDF 15 :DhCpmFc(-), DhCpmFc(+)(L351C)-G₄GDF15:DhCpmFc(-)(L351C), DhCpmFc(+)(S354C)-G₄-GDF15:DhCpmFc(-)(Y349C), CpmFc(-)-(G₄S)₄-GDF15:CpmFc(+), Fc-(G₄S)₈-Fc-GS(G₄S)₄-GDF15, Fc-(G₄S)₃-FcGS(G₄S)₄-GDF15 and Fc-(G₄S)₅-Fc-GS(G₄S)₄-GDF15.

In some embodiments, the dimer is not selected from the group consisting of

DhCpmF c(-)-(G₄S)₄-GDF 15 :DhCpmF c(+), DhCpmF c(+)-(G₄S)₄-GDF 15 :DhCpmF c(-),

DhCpmFc(-)-(G₄S)₄-GDF 15 (H6D):DhCpmFc(+), DhCpmFc(+)-(G₄S)₄GDF15 (H6D) :DhCpmFc(-), DhCpmFc(+)-(G₄S)₄-GDF 15 (N3Q):DhCpmFc(-), DhCpmFc(+)GDF15 :DhCpmF c(-), DhCpmFc(+)-G₄-GDF 15 :DhCpmF c(-), DhCpmF c(+)-(G₄S)₂10 GDF15:DhCpmFc(-), DhCpmFc(+)-(G₄Q)₄-GDF15:DhCpmFc(-), DhCpmFc(+)(L351C)-G₄GDF15:DhCpmFc(-)(L351C) and DhCpmFc(+)(S354C)-G₄-GDF15:DhCpmFc(-)(Y349C).

In some embodiments, the fusion protein is not a selected from the group consisting of Fc-(G₄S)₈-Fc-GS(G₄S)₄-GDF15, Fc-(G₄S)₃-Fc-GS(G₄S)₄-GDF15 and Fc-(G₄S)₅-FcGS(G₄S)₄-GDF15.

In some embodiments, the dimer is not selected from the group consisting of

DhCpmFc(+)(L351C)-G₄-GDF15:DhCpmFc(-)(L351C) and DhCpmFc(+)(S354C)-G₄GDF15 :DhCpmFc(-)(Y349C).

In some embodiments, the dimer is not DhCpmFc(-)-(G₄S)₄-GDF15:DhCpmFc(+), DhCpmFc(+)-(G₄S)₄-GDF15:DhCpmFc(-), DhCpmFc(-)-(G₄S)₄-GDF15(H6D):DhCpmFc(+),

DhCpmFc(+)-(G₄S)₄-GDF15(H6D):DhCpmFc(-), DhCpmFc(+)-(G₄S)₄GDF15 (N3Q) :DhCpmF c(-), DhCpmF c(+)-GDF 15 :DhCpmF c(-), DhCpmF c(+)-G₄GDF15 :DhCpmF c(-), DhCpmF c(+)-(G₄S)₂-GDF 15 :DhCpmF c(-), DhCpmF c(+)-(G₄Q)₄GDF15 :DhCpmFc(-), DhCpmFc(+)(L351 C)-G₄-GDF 15 :DhCpmFc(-)(L351C),

DhCpmFc(+)(S354C)-G₄-GDF15:DhCpmFc(-)(Y349C), CpmFc(-)-(G₄S)₄25 GDF15:CpmFc(+), Fc-(G₄S)₈-Fc-GS(G₄S)₄-GDF15, Fc-(G₄S)₃-Fc-GS(G₄S)₄-GDF15 or Fc(G₄S)₅-Fc-GS(G₄S)₄-GDF 15.

In some embodiments, the dimer is not DhCpmFc(-)-(G₄S)₄-GDF15:DhCpmFc(+), DhCpmFc(+)-(G₄S)₄-GDF15:DhCpmFc(-), DhCpmFc(-)-(G₄S)₄-GDF15(H6D):DhCpmFc(+), DhCpmFc(+)-(G₄S)₄-GDF15(H6D):DhCpmFc(-), DhCpmFc(+)-(G₄S)₄30 GDF15(N3Q):DhCpmFc(-), DhCpmFc(+)-GDF15:DhCpmFc(-), DhCpmFc(+)-G₄GDF15 :DhCpmF c(-), DhCpmF c(+)-(G₄S)₂-GDF 15 :DhCpmF c(-), DhCpmF c(+)-(G₄Q)₄GDF15 :DhCpmFc(-), DhCpmFc(+)(L3 51 C)-G₄-GDF 15 :DhCpmFc(-)(L351C) or

DhCpmFc(+)(S354C)-G₄-GDF15:DhCpmFc(-)(Y349C).

In some embodiments, the fusion protein is not selected from the group consisting of

Fc-(G₄S)₈-Fc-GS(G₄S)₄-GDF15, Fc-(G₄S)₃-Fc-GS(G₄S)₄-GDF15 and Fc-(G₄S)₅-FcGS(G₄S)₄-GDF15.

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In some embodiments, the fusion protein is not selected from the group consisting of DhCpmFc(+)(L351C)-G₄-GDF15:DhCpmFc(-)(L351C) and DhCpmFc(+)(S354C)-G₄GDF15 :DhCpmFc(-)(Y349C).

In some embodiments, the dimer is not DhCpmFc(-)-(G₄S)₄-GDF15:DhCpmFc(+). In 5 some embodiments, the dimer is not DhCpmFc(+)-(G₄S)₄-GDF15:DhCpmFc(-). In some embodiments, the dimer is not DhCpmFc(-)-(G₄S)₄-GDF15(H6D):DhCpmFc(+). In some embodiments, the dimer is not DhCpmFc(+)-(G₄S)₄-GDF15(H6D):DhCpmFc(-). In some embodiments, the dimer is not DhCpmFc(+)-(G₄S)₄-GDF15(N3Q):DhCpmFc(-). In some embodiments, the dimer is not DhCpmFc(+)-GDF15:DhCpmFc(-). In some embodiments, the dimer is not DhCpmFc(+)-G₄-GDF15:DhCpmFc(-). In some embodiments, the dimer is not DhCpmFc(+)-(G₄S)2-GDF15:DhCpmFc(-). In some embodiments, the dimer is not

DhCpmFc(+)-(G₄Q)₄-GDF15:DhCpmFc(-). In some embodiments, the dimer is not

DhCpmFc(+)(L351C)-G₄-GDF15:DhCpmFc(-)(L351C). In some embodiments, the dimer is not DhCpmFc(+)(S354C)-G₄-GDF15:DhCpmFc(-)(Y349C). In some embodiments, the dimer is not CpmFc(-)-(G₄S)₄-GDF15:CpmFc(+). In some embodiments, the dimer is not Fc-(G₄S)₈Fc-GS(G₄S)₄-GDF15. In some embodiments, the dimer is not Fc-(G₄S)₃-Fc-GS(G₄S)₄GDF15. In some embodiments, the dimer is not Fc-(G₄S)₅-Fc-GS(G₄S)₄-GDF15.

Also provided herein are fusion proteins comprising a GDF15 polypeptide or a GDF15 mutant polypeptide and a human serum albumin (HSA) polypeptide. In a further embodiment, the HSA polypeptide the sequence of SEQ ID NO:110. In another embodiment, the GDF15 polypeptide or a GDF15 mutant polypeptide comprises a sequence selected from the group consisting of SEQ ID NOs:4, 8, 12, 25, 52 and 55. In another embodiment, the fusion protein further comprises a polypeptide linker, joining the GDF15 polypeptide or GDF15 mutant polypeptide to the HSA polypeptide. In one embodiment, the polypeptide linker has a sequence selected from the group consisting of SEQ ID NOs:18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125, 128. In one embodiment, the fusion protein comprises two or more HSA polypeptides. In one embodiment, the fusion protein comprises a sequence selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127 and 130.

Also provided herein are dimers comprising (i) a first polypeptide chain comprising a fusion protein comprising a first GDF15 region and a first HSA polypeptide, and (ii) a second polypeptide chain comprising a second HSA polypeptide. In some embodiments, the second polypeptide chain further comprises a second GDF15 region. In some embodiments, the dimer is a heterodimer (i.e., the first and second polypeptide chain have different sequences).

In some embodiments, the dimer is a homodimer (i.e., the first and second polypeptide chain have the same sequence). In some embodiments, the first polypeptide chain comprises a sequence selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127 and

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130. In some embodiments, the second polypeptide chain comprises a sequence selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127 and 130. In one embodiment, the first and second polypeptide chains are non-covalently associated. In another embodiment, the first and second polypeptide chains are covalently associated. In one embodiment, the second polypeptide chain comprises a second GDF15 region and first and second polypeptide chains are covalently associated via disulfide bonds between their respective GDF15 regions. In another embodiment, the first and second polypeptide chains are associated by both covalent and non-covalent interactions.

Also provided herein are dimers comprising (i) a first polypeptide chain comprising a 10 fusion protein comprising a first GDF15 region and an HSA polypeptide, and (ii) a second polypeptide chain comprising a second GDF15 region. In some embodiments, the first polypeptide chain comprises a sequence selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127 and 130. In some embodiments, the second polypeptide chain comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 8, 12, 25, 52 and

55. In one embodiment, the first and second polypeptide chains are non-covalently associated.

In another embodiment, the first and second polypeptide chains are covalently associated. In another embodiment, the first and second polypeptide chains are associated by both covalent and non-covalent interactions.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graphic depicting of a knob-hole construct comprising a dimer of two

DhknobF c-(G4S)4-GDF 15 :DhholeF c heterodimers.

Figure 2 is a graphic depicting a DhMonoFc construct comprising a dimer of two DhMonoFc-(G₄S)4-GDF15 fusion proteins.

Figure 3 is a graphic depicting a HemiFc construct comprising a dimer of two

GGGFc-(G4S)4-Fc-S(G₄S)4-GDF15 fusion proteins.

Figure 4 is a graphic depicting a charged pair (delHinge) construct comprising a dimer of two DhCpmFc(-)-(G4S)2-GDF15:DhCpmFc(+) heterodimers.

Figure 5 is a graphic depicting a charged pair (delHinge) cysteine clamp construct comprising a dimer of two DhCpmFc(-)(L351C)-(G4S)₂-GDF15:DhCpmFc(-)(L351C) heterodimers.

Figure 6 is a graphic depicting an HSA construct comprising a dimer of two HSA(G₄S)₄-GDF15 fusion proteins.

Figure 7 is a plot showing the effect on food intake (g food/g body weight (BW) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhknobFc35 G4-GDF15 :DhholeF c heterodimer.

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Figure 8 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Fc-(G₄S)₄-GDF15 fusion protein.

Figure 9 is a plot showing the effect on food intake (g food/g body weight) of ob/ob 5 mice as a function of dose (log [g construct/kg BW]) using a dimer of the Fc-(G₄S)₄GDF15(H6D) fusion protein.

Figure 10 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Fc-(G₄S)₄-Fc(G₄S)₄-GDF15 fusion protein.

Figure 11 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhFc-(G₄S)₅-DhFc(G₄S)₄-GDF15 fusion protein.

Figure 12 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(+)-(lK)15 GDF 15 :DhCpmFc(-) heterodimer.

Figure 13 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)GDF15:DhCpmFc(+) heterodimer.

Figure 14 is a plot showing the effect on food intake (g food/g body weight) of ob/ob 20 mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)GDF15(N3D): DhCpmF c (+) heterodimer.

Figure 15 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)GDF15 (Ndel3) :DhCpmFc(+) heterodimer.

Figure 16 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)-G₄GDF15(N3D): DhCpmF c (+) heterodimer.

Figure 17 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)-G₄S30 GDF 15 :DhCpmF c(+) heterodimer.

Figure 18 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄S)₂-GDF 15 :DhCpmF c(+) heterodimer.

Figure 19 is a plot showing the effect on food intake (g food/g body weight) of ob/ob 35 mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄S)₂-GDF 15(N3D):DhCpmF c(+) heterodimer.

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Figure 20 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄Q)₂-GDF 15 (N3 D) :DhCpmF c(+) heterodimer.

Figure 21 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)-G₄PGDF15:DhCpmFc(+) heterodimer.

Figure 22 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄P)₂-GDF 15 :DhCpmF c(+) heterodimer.

Figure 23 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)-G₄QGDF15:DhCpmFc(+) heterodimer.

Figure 24 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄Q)₂-GDF 15 (N3D) :DhCpmF c(+) heterodimer.

Figure 25 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(G₄Q)₂-GDF 15 (Ndel3) :DhCpmF c(+) heterodimer.

Figure 26 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmF c(+)(Y349C)-GDF 15 (N3D) :DhCpmF c(-)(S354C) heterodimer.

Figure 27 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C) heterodimer.

Figure 28 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) heterodimer.

Figure 29 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) heterodimer.

Figure 30 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-G₄-GDF15(N3D):DhCpmFc(+)(S354C) heterodimer.

Figure 31 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-(G₄S)₂-GDF15(N3D):DhCpmFc(+)(S354C) heterodimer.

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Figure 32 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(Y349C)-(G₄Q)₂-GDF15(N3D):DhCpmFc(+)(S354C) heterodimer.

Figure 33 is a plot showing the effect on food intake (g food/g body weight) of ob/ob 5 mice as a function of dose (log [g construct/kg BW]) using a dimer of the

DhCpmFc(-)(L3 51 C)-(G₄S)₂-GDF 15 :DhCpmFc(+)(L351C) heterodimer.

Figure 34 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSAGSAAQAAQQGS-GDF15 fusion protein.

Figure 35 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSAGSPAPAPGS-GDF15 fusion protein.

Figure 36 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSA15 GS(AAQAAQQ)₂GS-GDF15 fusion protein.

Figure 37 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSAGS(PAPAP)₂GS-GDF15 fusion protein.

Figure 38 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSA-GDF15 fusion protein.

Figure 39 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSAGGNAEAAAKEAAAKEAAAKAGG-GDF15 fusion protein.

Figure 40 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the HSA-(G₄S)₆GDF15 fusion protein.

Figure 41 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the

DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G) heterodimer.

Figure 42 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmF c(-)(N297G)-GDF 15 (N3D) :DhCpmF c(+)(N297G) heterodimer.

Figure 43 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C) heterodimer.

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Figure 44 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C) heterodimer.

Figure 45 is a plot showing the effect on food intake (g food/g body weight) of ob/ob 5 mice as a function of dose (log [g construct/kg BW]) using a dimer of the

DhCpmFc(-)(N297G)(L3 51 C)-GDF 15 (Ndel3) :DhCpmFc(+)(N297G)(L3 51C) heterodimer.

Figure 46 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(N297G)(L3 51 C)-GDF 15 (N3D):DhCpmFc(+)(N297G)(L3 51C) heterodimer.

Figure 47 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C) heterodimer.

Figure 48 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the CpmFc(-)(N297G)15 GDF15(Ndel3):CpmFc(+)(N297G) heterodimer.

Figure 49 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(N297G) heterodimer.

Figure 50 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Dh3CpmFc(-)GDF15 (N3 D) :Dh3CpmF c(+)(N297G) heterodimer.

Figure 51 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(N297G)(S354C) heterodimer.

Figure 52 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the Dh3CpmFc(-)(Y349C)-GDF15(N3D): Dh3CpmFc(-)(N297G)(S354C) heterodimer.

Figure 53 is a plot showing the effect on food intake (g food/g body weight) of ob/ob mice as a function of dose (log [g construct/kg BW]) using a dimer of the

DhMonoFc(N297G)-GDF 15 fusion protein.

Figure 54 is a plot of body weight (g) as a function of time (days post 1^st injection) for vehicle, 0.1 nmol, 1 nmol and 10 nmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer, and 0.1 nmol, 1 nmol and 10 nmol of a dimer of the Dh3ComFc(-)-GDF15(Ndel3) heterodimer.

Figure 55 is a bar graph of area under the curve (AUC) for a glucose tolerance test at week 2 of treatment with (a) vehicle (b) 10 mmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer (c) 1 mmol of a dimer of the Dh3CpmFc(-)13

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GDF15(N3D):Dh3CpmFc(+) heterodimer, (d) 0.1 mmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer, (e) 10 mmol of a dimer of the Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) heterodimer (g) 1 mmol of a dimer of the Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) heterodimer, or (g) 0.1 mmol of a dimer of the Dh3CpmFc(-)5 GDF15(Ndel):Dh3CpmFc(+) heterodimer.

Figure 56 is a bar graph of insulin (ng/mL) (fed) at week 3 of treatment with (a) vehicle (b) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer (c) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (d) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (e) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer (g) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer, or (g) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel):Dh3CpmFc(+) heterodimer.

Figure 57 is a bar graph of triglycerides (mg/mL) (fed) at week 3 of treatment with (a) vehicle (b) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer (c) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (d) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (e) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer (g) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer, or (g) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel):Dh3CpmFc(+) heterodimer.

Figure 58 is a bar graph of cholesterol (mg/mL) (fed) at week 3 of treatment with (a) vehicle (b) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer (c) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (d) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimer, (e) 10 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer (g) 1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimer, or (g) 0.1 mmol of a dimer of the Dh3CpmFc(-)-GDF15(Ndel):Dh3CpmFc(+) heterodimer.

Figure 59 is a bar graph of area under the curve (AUC) for a glucose tolerance test at week 5 of treatment with (a) vehicle (b) 10 mmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer (c) 1 mmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer, (d) 0.1 mmol of a dimer of the Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer, (e) 10 mmol of a dimer of the Dh3CpmFc(-)35 GDF15(Ndel3):Dh3CpmFc(+) heterodimer (g) 1 mmol of a dimer of the Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) heterodimer, or (g) 0.1 mmol of a dimer of the Dh3CpmFc(-)GDF15 (Ndel):Dh3CpmFc(+) heterodimer.

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Figure 60 is a bar graph showing SPR Binding (RU) with respect to FcyRI, FcyRIIIA and FcyRIIA for (a) a dimer of DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+), (b) a dimer of DhCpmFc(-)(Y349C)-GDF15(Ndel3): DhCpmFc(+)(S354C); (c) a dimer of Dh3CpmFc(-)GDF15(Ndel3); (d) a dimer of Dh3CpmFc(-)(Y349C)-GDF15(Ndel3)-Dh3CpmFc(+)(S354C); 5 (e) a dimer of Dh3CpmFc(-)-GDF15(N3D); and (f) a dimer of Dh3CpmFc(-)(Y349C)GDF15(N3D):Dh3CpmFc(+)(S354C) (from left to right with respect to each receptor).

Figure 61 is a bar graph showing DSC first Tm (°C) with respect to (a) (for pair of bars captioned “N3D”), a dimer of DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) and a dimer of Dh3CpmFc(-)-GDF15(N3D):DhCpmFc(+); (b) (for the pair of bars captioned “Ndel3”), a 0 dimer of DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+) and a dimer of Dh3CpmFc(-)GDF15(Ndel3):DhCpmFc(+); (c) (for the pair of bars captioned “N3D+CC”), a dimer of DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) and a dimer of Dh3CpmFc()(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C); and (d) (for the pair of bars captioned “Ndel3+CC”), a dimer of DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) and a 5 dimer of Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C).

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the present invention provides a fusion protein comprising a GDF 15 region and an Fc domain, wherein the Fc domain comprises an amino acid sequence of

SEQ ID NO: 220 and wherein the N-terminus of the Fc domain consists of residues 1 to 210 of SEQ ID NO: 220.

According to a second aspect, the present invention provides a fusion protein comprising a GDF 15 region and an Fc domain, wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 227 and wherein the N-terminus of the Fc domain consists of residues

1 to 210 of SEQ ID NO: 227.

According to a third aspect, the present invention provides a dimer comprising (i) a first protein comprising a fusion protein of the invention, and (ii) a second protein comprising an Fc domain.

According to a fourth aspect, the present invention provides a tetramer comprising (a) a first dimer of the invention and (b) a second dimer of the invention.

According to a fifth aspect, the present invention provides a method of treating a metabolic disorder characterised by increased body weight or food intake, or elevated insulin,

2014296107 14 Jun 2018 triglyceride, cholesterol or glucose levels which comprises administering to a subject an effective amount of a fusion protein of the invention.

According to a sixth aspect, the present invention provides a method of treating diabetes, obesity, dyslipidemia or diabetic nephropathy comprising administering to a subject 5 an effective amount of a fusion protein of the invention.

According to a seventh aspect, the present invention provides a method of treatment to reduce food intake, body weight, insulin levels, triglyceride levels, cholesterol levels or glucose levels which comprises administering to a subject an effective amount of a fusion protein of the invention.

According to an eighth aspect, the present invention provides a method of treating a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels which comprises administering to a subject an effective amount of a dimer of the invention.

According to a ninth aspect, the present invention provides a method of treating diabetes, obesity, dyslipidemia or diabetic nephropathy comprising administering to a subject an effective amount of a dimer of the invention.

According to a tenth aspect, the present invention provides a method of treatment to reduce food intake, body weight, insulin levels, triglyceride levels, cholesterol levels or glucose levels which comprises administering to a subject an effective amount of a dimer of the invention.

According to an eleventh aspect, the present invention provides a method of treating a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels which comprises administering to a subject an effective amount of a tetramer of the invention.

According to a twelfth aspect, the present invention provides a method of treatment to reduce food intake, body weight, insulin levels, triglyceride levels, cholesterol levels or glucose levels which comprises administering to a subject an effective amount of a tetramer of the invention.

According to a thirteenth aspect, the present invention provides use of a fusion protein of the invention in the manufacture of a medicament for the treatment of a metabolic disorder.

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According to a fourteenth aspect, the present invention provides use of the fusion protein of the invention in the manufacture of a medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

According to a fifteenth aspect, the present invention provides use of a fusion protein of 5 the invention in the manufacture of a medicament for reducing: food intake; body weight; insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

According to a sixteenth aspect, the present invention provides use of a dimer of the invention in the manufacture of a medicament for the treatment of a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, 0 cholesterol or glucose levels.

According to a seventeenth aspect, the present invention provides use of the dimer of the invention in the manufacture of a medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

According to an eighteenth aspect, the present invention provides use of a dimer of the 5 invention in the manufacture of a medicament for reducing: food intake; body weight; insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

According to a nineteenth aspect, the present invention provides use of a tetramer of the invention in the manufacture of a medicament for the treatment of a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels.

According to a twentieth aspect, the present invention provides use of the tetramer of the invention in the manufacture of a medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

According to a twenty-first aspect, the present invention provides use of a tetramer of 25 the invention in the manufacture of a medicament for reducing: food intake; body weight;

insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

The instant disclosure provides fusion proteins comprising a GDF15 polypeptide or a GDF15 mutant polypeptides and constructs comprising such fusion proteins. Also provided is the generation and uses of the disclosed molecules, for example in treating a metabolic disorder, such as Type 2 diabetes, elevated glucose levels, elevated insulin levels, dyslipidemia or obesity. GDF15 polypeptides, GDF15 mutant polypeptides, and certain polypeptide constructs comprising GDF15 polypeptides and GDF15 mutant polypeptides, are described in co-owned

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PCT/US2012/032415, filed 04/05/2012, and PCT/2013/023465, filed 01/28/2013, both of which are expressly incorporated by reference herein for any purpose.

Recombinant polypeptide and nucleic acid methods used herein, including in the Examples, are generally those set forth in Sambrook et al., Molecular Cloning: A Laboratory

Manual (Cold Spring Harbor Laboratory Press, 1989) or Current Protocols in Molecular

Biology (Ausubel et al., eds., Green Publishers Inc. and Wiley and Sons 1994).

L_General Definitions

Following convention, as used herein “a” and “an” mean “one or more” unless specifically indicated otherwise.

As used herein, the terms “amino acid” and “residue” are interchangeable and, when used in the context of a peptide or polypeptide, refer to both naturally-occurring and synthetic

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PCT/US2014/049254 amino acids, as well as amino acid analogs, amino acid mimetics and non-naturally-occurring amino acids that are chemically similar to the naturally-occurring amino acids.

The terms “naturally-occurring amino acid” and “naturally encoded amino acid” are used interchangeably and refer to an amino acid that is encoded by the genetic code, as well as those amino acids that are encoded by the genetic code that are modified after synthesis, e.g., hydroxyproline, γ-carboxy glutamate, and O-phosphoserine.

An “amino acid analog” is a compound that has the same basic chemical structure as a naturally-occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs can have modified R groups (e.g., norleucine) or modified peptide backbones, but will retain the same basic chemical structure as a naturallyoccurring amino acid.

An “amino acid mimetic” is a chemical compound that has a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally-occurring amino acid. Examples include a methacryloyl or acryloyl derivative of an amide, β-, γ-, δ-imino acids (such as piperidine-4-carboxylic acid) and the like.

The terms “non-naturally-occurring amino acid” and “non-naturally encoded amino acid” are used interchangeably and refer to a compound that has the same basic chemical structure as a naturally-occurring amino acid, but is not incorporated into a growing polypeptide chain by the translation complex. “Non-naturally-occurring amino acid” also includes, but is not limited to, amino acids that occur by modification (e.g., posttranslational modifications) of a naturally encoded amino acid (including but not limited to, the 20 common amino acids) but are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. A non-limiting lists of examples of non25 naturally-occurring amino acids that can be inserted into a polypeptide sequence or substituted for a wild-type residue in polypeptide sequence include β-amino acids, homoamino acids, cyclic amino acids and amino acids with derivatized side chains. Examples include (in the L-form or D-form; abbreviated as in parentheses): citrulline (Cit), homocitrulline (hCit), Να-methylcitrulline (NMeCit), Να-methylhomocitrulline (Na30 MeHoCit), ornithine (Om), Na-Methylomithine (Na-MeOm or NMeOm), sarcosine (Sar), homolysine (hLys or hK), homoarginine (hArg or hR), homoglutamine (hQ), Να-methylarginine (NMeR), Na-methylleucine (Να-MeL or NMeL), N-methylhomolysine (NMeHoK), Να-methylghitamine (NMeQ), norleucine (Nle), norvaline (Nva), 1,2,3,4tetrahydroisoquinoline (Tic), Octahydroindole-2-carboxylic acid (Oic), 3-(l-naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2-indanylglycine (Igl), para-iodophenylalanine (pl-Phe), para-aminophenylalanine (4AmP or 4-Amino-Phe), 4guanidino phenylalanine (Guf), glycyllysine (abbreviated “K(NE-glycyl)” or “K(glycyl)” or

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PCT/US2014/049254 “K(gly)”), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or Amino-Phe), benzylphenylalanine (benzylphe), γ-carboxyglutamic acid (γ-carboxyglu), hydroxyproline (hydroxypro), p-carboxyl-phenylalanine (Cpa), α-aminoadipic acid (Aad), Να-methyl valine (NMeVal), Ν-α-methyl leucine (NMeLeu), Να-methylnorleucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg), a, βdiaminopropionoic acid (Dpr), a, γ-diaminobutyric acid (Dab), diaminopropionic acid (Dap), cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), β, β-diphenyl-alanine (BiPhA), aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine; 4Bip), a-aminoisobutyric acid (Aib), beta-alanine, beta-aminopropionic acid, piperidinic acid, aminocaprioic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, Nethylglycine, N-ethylaspargine, hydroxylysine, allo-hydroxylysine, isodesmosine, alloisoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), γ-carboxyglutamate, ε-Ν,Ν,Ν-trimethyllysine, ε-Ν-acetyllysine, O-phosphoserine, Nacetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-methylarginine, 415 Amino-O-Phthalic Acid (4APA), N-acetylglucosaminyl-L-serine, N-acetylglucosylaminyl-Lthreonine, O-phosphotyrosine and other similar amino acids, and derivatized forms of any of those specifically listed.

Also included in the definition of “non-naturally-occurring amino acid’’ is any amino acid comprising the structure

R

.. ..........,..

LOOM:

wherein the R group is any substituent other than the one used in the twenty natural amino acids.

In some embodiments, the non-naturally encoded amino acid comprises a carbonyl group. In some embodiments, the non-naturally encoded amino acid has the structure:

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PCT/US2014/049254 (CHg/RjCORy

wherein n is 0-10; Ri is an alkyl, aryl, substituted alkyl, or substituted aryl; R₂ is H, an alkyl, aryl, substituted alkyl, and substituted aryl; and R₃ is H, an amino acid, a polypeptide, or an amino terminus modification group, and R4 is H, an amino acid, a polypeptide, or a carboxy terminus modification group.

In some embodiments, the non-naturally encoded amino acid comprises an aminooxy group. In some embodiments, the non-naturally encoded amino acid comprises a hydrazide group. In some embodiments, the non-naturally encoded amino acid comprises a hydrazine group. In some embodiments, the non-naturally encoded amino acid residue comprises a semicarbazide group.

In some embodiments, the non-naturally encoded amino acid residue comprises an azide group. In some embodiments, the non-naturally encoded amino acid has the structure:

RXX cor₃ wherein n is 0-10; Ri is an alkyl, aryl, substituted alkyl, substituted aryl or not present; X is O, 15 N, S or not present; m is 0-10; R₂ is H, an amino acid, a polypeptide, or an amino terminus modification group, and R₃ is H, an amino acid, a polypeptide, or a carboxy terminus modification group.

In some embodiments, the non-naturally encoded amino acid comprises an alkyne group. In some embodiments, the non-naturally encoded amino acid has the structure:

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PCT/US2014/049254 (CH^RjXCCHjJrCC.H

MN CORi wherein n is 0-10; Ri is an alkyl, aryl, substituted alkyl, or substituted aryl; X is Ο, N, S or not present; m is 0-10, R₂is H, an amino acid, a polypeptide, or an amino terminus modification group, and R₃ is H, an amino acid, a polypeptide, or a carboxy terminus modification group.

The term “substituted” means that a hydrogen atom on a molecule or group is replaced with a group or atom, which is referred to as a substituent. Typical substituents include: halogen, Ci-₈alkyl, hydroxyl, Ci-₈alkoxy, -NR^XR^X, nitro, cyano, halo or perhaloCi8alkyl, C2-8alkenyl, C2-8alkynyl, -SR^X, -S(=O)2R^X, -C(=O)OR^X, -C(=O)R^X, wherein each R^x is independently hydrogen or Ci-C₈ alkyl. It is noted that when the substituent is -NR^XR^X, the

R^x groups may be joined together with the nitrogen atom to form a ring.

The term alkyl means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as Ci-₈alkyl.

The term alkoxy means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. Common alkoxy groups are Ci-₈alkoxy.

The term halogen or “halo” means chlorine, fluorine, bromine or iodine.

The term alkenyl means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds. Representative examples alkenyl groups include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. Common alkenyl groups are C2-₈alkenyl.

The term alkynyl means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds. Representative examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl. Common alkynyl groups are C₂-₈ alkynyl.

The term cyeloalkyl means a cyclic, nonaromatic hydrocarbon. Examples of cyeloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cyeloalkyl group can contain one or more double bond. Examples of cyeloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cyeloalkyl groups are C₃-₈ cyeloalkyl groups.

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The term perfluoroalkyl means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms. Common perfluoroalkyl groups are Cisperfluoroalkyl. An example of a common perfluoroalkyl group is -CF₃.

The term acyl means a group derived from an organic acid by removal of the 5 hydroxy group (-OH). For example, the acyl group CH₃C(=O)- is formed by the removal of the hydroxy group from CH₃C(=O)OH.

The term aryl means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.

The term heteroatom as used herein means an oxygen, nitrogen or sulfur atom.

The term heteroaryl means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyi, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five to thirteen membered rings that contain from 1 to 4 heteroatoms. Heteroaryl groups that are five and six membered rings that contain 1 to 3 heterotaoms are particularly common.

The term heterocycloalkyl means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran. Common heterocycloalkyl groups are three to ten membered rings containing from 1 to 4 heteroatoms. Heterocycloalkyl groups that are five and six membered rings that contain 1 to 2 heterotaoms are particularly common.

It is also noted that the cyclic ring groups, i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.

Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.

Representative examples of partially saturated, fully saturated or fully unsaturated 35 five to eight membered rings, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl,

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PCT/US2014/049254 thiazoiyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-l,2-oxathiolyl, 1,2,3oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3,4oxadiazolyl, 1,2,3-triazolyl, 1,2,4trizaolyl, 1,3,4-thiadiazolyl, 3H-l,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,45 dioxazolyl, 5H-l,2,5-oxathiazolyl, and 1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-l,2-oxazinyl, 2H-l,3-oxazinyl, 6H-l,3-oxazinyl,

6H-l,2-oxazinyl, 1,4-oxazinyl, 2H-l,2-oxazinyl, 4H-l,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-(3 oxathiazinyl, and 1,4,2oxadiazinyl.

Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4triazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, optionally having one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, lH-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-l,3-benzoxazinyl, 2H-l,4-benzoxazinyl, lH-2,3-benzoxazinyl, 4H-3,l-benzoxazinyl, 2H-l,2-benzoxazinyl and 4H-l,4-benzoxazinyl.

A cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term pyridyl includes 2-, 3-, or 4-pyridyl, and the term thienyl includes 2-, or 3-thienyl.

The term “isolated nucleic acid molecule’’ refers to a single or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases read from the 5’ to the 3’ end (e.g., a GDF 15 nucleic acid sequence provided herein), or an analog thereof, that has been separated from at least about 50 percent of polypeptides, peptides, lipids, carbohydrates, polynucleotides or other materials with which the nucleic acid is naturally found when total nucleic acid is isolated from the source cells. Preferably, an isolated nucleic acid molecule is substantially free from any other contaminating nucleic acid molecules or other molecules

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PCT/US2014/049254 that are found in the natural environment of the nucleic acid that would interfere with its use in polypeptide production or its therapeutic, diagnostic, prophylactic or research use.

The term “isolated polypeptide’’ refers to a polypeptide (e.g., a GDF15 polypeptide or GDF15 mutant polypeptide provided herein) that has been separated from at least about 50 percent of polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other materials with which the polypeptide is naturally found when isolated from a source cell. Preferably, the isolated polypeptide is substantially free from any other contaminating polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic or research use.

The term “encoding’’ refers to a polynucleotide sequence encoding one or more amino acids. The term does not require a start or stop codon. An amino acid sequence can be encoded in any one of the different reading frames provided by a polynucleotide sequence.

The terms “identical’’ and percent “identity,’’ in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same. “Percent identity’’ means the percent of identical residues between the amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest of the molecules being compared. For these calculations, gaps in alignments (if any) can be addressed by a particular mathematical model or computer program (i.e., an “algorithm’’). Methods that can be used to calculate the identity of the aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, A. M., ed.), (1988) New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, D. W., ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; von Heinje, G., (1987) Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence

Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press; andCarillo et al., (1988) SIAM J. Applied Math. 48:1073.

In calculating percent identity, the sequences being compared are aligned in a way that gives the largest match between the sequences. The computer program used to determine percent identity is the GCG program package, which includes GAP (Devereux et al., (1984)

Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, WI). The computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined. The sequences are aligned for optimal matching of their respective amino acid or nucleotide (the “matched span’’, as determined by the algorithm). A gap opening penalty (which is calculated as 3x the average diagonal, wherein the “average diagonal’’ is the average of the diagonal of the comparison matrix being used; the “diagonal’’ is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (which is usually

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1/10 times the gap opening penalty), as well as a comparison matrix such as PAM 250 or

BLOSUM 62 are used in conjunction with the algorithm. In certain embodiments, a standard comparison matrix (see, Dayhoff et al., (1978) Atlas of Protein Sequence and Structure

5:345-352 for the PAM 250 comparison matrix; Henikoff et al., (1992) Proc. Natl. Acad. Sci.

U.S.A. 89:10915-10919 for the BLOSUM 62 comparison matrix) is also used by the algorithm.

Recommended parameters for determining percent identity for polypeptides or nucleotide sequences using the GAP program are the following:

Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-13:

Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, supra',

Gap Penalty: 12 (but with no penalty for end gaps)

Gap Length Penalty: 4

Threshold of Similarity: 0

Certain alignment schemes for aligning two amino acid sequences can result in matching of only a short region of the two sequences, and this small aligned region can have very high sequence identity even though there is no significant relationship between the two full-length sequences. Accordingly, the selected alignment method (e.g., the GAP program) can be adjusted if so desired to result in an alignment that spans at least 50 contiguous amino acids of the target polypeptide.

The term “GDF15 polypeptide” means a naturally-occurring or “wild-type” GDF15 expressed in a mammal, including without limitation, a human, rabbit, monkey (e.g. cynomolgous monkey), dog, rat mouse or pig. In one aspect, GDF15 polypeptide refers to any full-length GDF15, e.g., SEQ ID NO:4, which consists of 308 amino acid residues and which is encoded by the nucleotide sequence SEQ ID NO:3; any form comprising the active and prodomains of the polypeptide, e.g., SEQ ID NO:8, which consists of 279 amino acid residues and which is encoded by the nucleotide sequence SEQ ID NO:7, and in which the 29 amino acid residues at the amino-terminal end of the full-length GDF15 (i.e., which constitute the signal peptide) have been removed; and any form of GDF15 comprising the active domain from which the prodomain and signal sequence have been removed, e.g., SEQ ID NO: 12, which consists of 112 amino acid residues and which is encoded by the nucleotide sequence SEQ ID NO:11, in which the signal sequence and the prodomain have been removed. GDF15 polypeptides can but need not comprise an amino-terminal methionine, which may be introduced by engineering or as a result of a bacterial expression process.

The term “GDF15 mutant polypeptide” refers to a GDF15 polypeptide (e.g., SEQ ID

NOs:4, 8 or 12) that has been modified. Such modifications include, but are not limited to, one or more amino acid substitutions, including substitutions with non-naturally-occurring amino acids non-naturally-occurring amino acid analogs and amino acid mimetics, additions

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PCT/US2014/049254 or deletions. In one aspect, the term “GDF15 mutant polypeptide” refers to a GDF15 polypeptide in which at least one residue normally found at a given position of the naturallyoccurring GDF15 polypeptide is deleted or is replaced by a residue not normally found at that position in the naturally-occurring GDF15 polypeptide. In some cases it will be desirable to replace a single residue normally found at a given position in the sequence of a naturallyoccurring GDF15 polypeptide with more than one residue that is not normally found at the position; in still other cases it may be desirable to maintain the sequence of the naturallyoccurring GDF15 polypeptide and insert one or more residues at a given position in the protein; in still other cases it may be desirable to delete a given residue entirely; all of these constructs are encompassed by the term “GDF15 mutant polypeptide.”

In various embodiments, a GDF 15 mutant polypeptide comprises an amino acid sequence that is at least about 85 percent identical to a naturally-occurring GDF 15 polypeptide (e.g., SEQ ID NOs:4, 8 or 12). In other embodiments, a GDF 15 mutant polypeptide comprises an amino acid sequence that is at least about 90 percent, or about 95,

96, 97, 98, or 99 percent identical to a naturally-occurring GDF 15 polypeptide amino acid sequence (e.g., SEQ ID NOs:4, 8 or 12). Such GDF 15 mutant polypeptides preferably, but need not, possess at least one activity of a naturally-occurring GDF 15 polypeptide, such as the ability to lower blood glucose, insulin, triglyceride, or cholesterol levels; the ability to reduce body weight; the ability to improve glucose tolerance, lipid tolerance, or insulin sensitivity; or the ability to lower urine glucose and protein excretion.

The term “GDF 15 region” encompasses GDF 15 polypeptides and GDF 15 mutant polypeptides and sequences as defined above.

A GDF 15 polypeptide or a GDF 15 mutant polypeptide is preferably biologically active. In some instances, a GDF 15 polypeptide or a GDF 15 mutant polypeptide used to treat or ameliorate a metabolic disorder in a subject from or derived from a different species as the subject. In some instances, a GDF 15 polypeptide or a GDF 15 mutant polypeptide used to treat or ameliorate a metabolic disorder in a subject from or derived from the same species as the subject.

The term “native Fc” refers to molecule or sequence comprising the sequence of a non-antigen-binding fragment resulting from digestion of whole antibody, whether in monomeric or multimeric form. The original immunoglobulin source of the native Fc is preferably of human origin and may be any of the immunoglobulins, although IgGl and IgG2 are preferred. Native Fc's are made up of monomeric polypeptides that may be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association.

The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, IgE) or subclass (e.g., IgGl, IgG2, IgG3, IgAl, IgGA2). One example of a native Fc is a disulfide-bonded dimer resulting

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PCT/US2014/049254 from papain digestion of an IgG (see Ellison et al. (1982), Nucleic Acids Res. 10: 4071-9).

The term “native Fe” as used herein is generic to the monomeric, dimeric, and multimeric forms.

The term “Fe variant” refers to a molecule or sequence that is modified from a native 5 Fe. Such modifications include, but are not limited to, one or more amino acid substitutions, including substitutions with non-naturally-occurring amino acids, non-naturally-occurring amino acid analogs and amino acid mimetics, deletions or additions. Thus, the term “Fe variant” comprises a molecule or sequence that is humanized from a non-human native Fe. Furthermore, a native Fe comprises sites that may be removed because they provide structural features or biological activity that are not required for the fusion molecules of the present invention. Thus, the term “Fe variant” comprises a molecule or sequence that lacks one or more native Fe sites or residues that affect or are involved in (1) disulfide bond formation, (2) incompatibility with a selected host cell (3) N-terminal heterogeneity upon expression in a selected host cell, (4) gly cosy lation, (5) interaction with complement, (6) binding to an Fe receptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC). Fe variants are described in further detail hereinafter. In various embodiments, an Fe variant comprises an amino acid sequence that is at least about 85 percent identical to a native Fe. In other embodiments, an Fe variant comprises an amino acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to a native Fe.

The term “Fe domain” encompasses native Fe and Fe variant molecules and sequences as defined above. As with Fe variants and native Fes, the term “Fe domain” includes molecules in monomeric or multimeric form.

The term “multimer” as applied to Fe domains or molecules comprising Fe domains refers to molecules having two or more polypeptide chains associated covalently, noncovalently, or by both covalent and non-covalent interactions. IgG molecules typically form dimers; IgM, pentamers; IgD, dimers; and IgA, monomers, dimers, trimers, or tetramers. Multimers may be formed by exploiting the sequence and resulting activity of the native Ig source of the Fe or by derivatizing such a native Fe.

The term “dimer” as applied to Fe domains or molecules comprising Fe domains refers to molecules having two polypeptide chains associated covalently, non-covalently or by both covalent and non-covalent interactions.

The term hinge or hinge region herein includes the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. The hinge region as referred to herein is a sequence region of 6-62 amino acids in length, only present in IgA, IgD and IgG, which encompasses the cysteine residues that bridge the two heavy chains.

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The “polypeptide linker’’ refers to a short polypeptide, generally from 1 to 30 amino acid residues in length, that covalently links together two polypeptides, typically via peptide bonds.

As used herein, the term HSA polypeptide encompasses a naturally-occurring “wild 5 type’’ human serum albumin. The term also includes various bioactive fragments and variants, fusion proteins, and modified forms of the wild type HSA protein. Such bioactive fragments or variants, fusion proteins, and modified forms of wild type HSA protein have at least a portion of the amino acid sequence of substantial sequence identity to the wild type HAS protein. In certain embodiments, such bioactive fragments or variants, fusion proteins, and modified forms of wild type HSA protein have an amino acid sequence that is at least about 85 percent identical to the wild type HSA. In other embodiments, such bioactive fragments or variants, fusion proteins, and modified forms of wild type HSA protein have an amino acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the wild type HAS.

II. Fc Fusions Comprising GDF15 Polypeptides or GDF15 Mutant Polypeptides, and Polynucleotides

A range of Fc fusion proteins comprising a GDF15 polypeptide or a GDF15 mutant polypeptide are provided herein. In some embodiments, the fusion proteins comprise a native

Fc. In some embodiments, the fusion proteins comprise an Fc domain that has been engineered.

In some embodiments, the GDF15 polypeptide- (or GDF15 mutant polypeptide-) containing Fc fusion proteins associate with another polypeptide chain consisting of or comprising an Fc domain to form a heterodimer. In some embodiments, two such heterodimers associate to form a heterotetramer. Some of these polypeptide constructs (i.e., GDF15 polypeptide- (or GDF15 mutant polypeptide-) containing Fc fusion proteins and multimers comprising one or more such GDF15 polypeptide- (or GDF15 mutant polypeptide) containing Fc fusion proteins) were studied empirically, as described in the Examples presented herein below.

Antibodies belong to the immunoglobulin class of proteins which includes IgG, IgA,

IgE, IgM, and IgD. The most abundant immunoglobulin class in human serum is IgG (Deisenhofer J 1981 Biochem 20:2361-2370; Huber R 1984 Behring Inst Mitt 76:1-14; Roux KH 1999 Int Arch Allergy Immunol 120:85-99). The IgG structure has four chains, two light and two heavy chains; each light chain has two domains and each heavy chain has four domains. The antigen binding site is located in the Fab domain (Fragment antigen binding) which contains a variable light (VL) and a variable heavy (VH) chain domain as well as constant light (LC) and constant heavy (CHI) chain domains. The CH2 and CH3 domain

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PCT/US2014/049254 region of the heavy chain is called Fc (Fragment crystallizable). The IgG molecule can be considered as a heterotetramer having two heavy chains that are held together by disulfide bonds (-S-S-) at the hinge region and two light chains. The number of hinge disulfide bonds varies among the immunoglobulin subclasses (Papadea C 1989 Crit Rev Clin Lab Sci 27:275 58). The FcRn binding site is located in the Fc domain of the antibody (Martin WL 2001 Mol

Cell 7:867-877), and thus the extended serum half-life property of the antibody is retained in the Fc fragment. The Fc domain alone can be thought of as a homodimer of heavy chains comprising CH2 and CH3 domains.

In certain preferred embodiments, the fusion proteins described herein comprise an 10 IgG Fc domain, derived from a wild-type human IgG Fc domain. By “wild-type” human IgG Fc, it is meant a sequence of amino acids that occurs naturally within the human population. Of course, just as the Fc sequences may vary slightly between individuals, one or more alterations may be made to a wild-type sequence and still remain within the scope of the invention. For example, the Fc domain may contain additional alterations that are not related to the present invention, such as a mutation in a glycosylation site or the inclusion of an unnatural amino acid. In certain embodiments, the polypeptide containing the CH3 region is an IgG molecule and further contains a CHI and CH2 domain. Exemplary human IgG sequences comprise the constant regions of IgGl, IgG2, IgG3 and IgG4. The Fc domain also may be comprised within the constant region of an IgA, IgD, IgE, and IgM heavy chain.

Some Fc fusion proteins containing GDF 15 polypeptide or GDF 15 mutant polypeptide, and multimers comprising such Fc fusion proteins include those described below.

II.A, DhMonoFc Constructs

The designations “Mono-” or “MonoFc domain” in the instant disclosure refer to an

Fc domain that has been engineered to reduce or prevent the formation of homodimers. In one embodiment, a MonoFc domain is provided by introducing a tyrosine to threonine mutation (Y349T) and two lysine to aspartic acid mutations (K392D and K409D) in a native Fc or Fc variant.

The C-terminal lysine (K447) optionally may be deleted in the MonoFc. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

A fusion protein is provided comprising a MonoFc domain and a GDF 15 region. Typically, the N-terminus of the GDF 15 region is linked, directly or via a polypeptide linker, to the C-terminus of the MonoFc domain. However, in some embodiments, the N-terminus of the MonoFc domain is linked, directly or via a polypeptide linker, to the C-terminus of the GDF 15 region.

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In certain embodiments, a dimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions. In some embodiments the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

The designations “DhMono-” or “DhMonoFc domain” in the instant disclosure refer 5 to an Fe domain from which all or part of the hinge region has been removed that has been engineered to reduce or prevent the formation of homodimers. In one embodiment, a DhMonoFc domain is provided introducing a tyrosine to threonine mutation (Y349T) and two lysine to aspartic acid mutations (K392D and K409D) in a native Fe or Fe variant from which all or part of the hinge region has been removed.

The C-terminal lysine (K447) optionally may be deleted in the DhMonoFc. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

A fusion protein is provided comprising a DhMonoFc domain and a GDF15 region. Typically, the N-terminus of the GDF15 region is linked, directly or via a polypeptide linker, to the C-terminus of the DhMonoFc domain. However, in some embodiments, the N-terminus of the DhMonoFc domain is linked, directly or via a polypeptide linker, to the C-terminus of the GDF15 region.

In certain embodiments, a dimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions. In some embodiments the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

II. A. 1 DhMonoFc-GDF15

The designation “MonoFc-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide, the N-terminus of which is linked directly to the C25 terminus of a MonoFc domain.

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two MonoFc domains (one each monomer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:22), and

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PCT/US2014/049254 (b) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ

ID NO: 12.

In a preferred embodiment, the fusion protein comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN

PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:46), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtgcgcgcaacggagaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:45).

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:46.

11.A.2 DhMonoFc-(G₄S)₄-GDF15

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The designation “DhMonoFc-(G4S)4-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc domain via a polypeptide linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc domain.

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two DhMonoFc domains (one each monomer) comprising the sequence of SEQ ID NO:22, (b) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ

ID NO: 12, and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:18) each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhMonoFc 15 domain.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 20 PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKS L S L S PGGGGGSGGGGSGGGGSGGGGSARNGDHCPLGPGRC CRLHTVRAS LEDLGWADWVL S PREVQVTMCIGAC PSQFRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID

NO:24), which is encoded by the nucleic acid sequence:

cacctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccc aaggacacccteatgatctcccggacccctgaggtcacatgcgtggtggt ggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacg gcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac agcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggct gaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagccc ccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacag gtgaccaccctgcccccatcccgggaggagatgaccaagaaccaggtcag

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PCT/US2014/049254 cctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagt gggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtg ctggactccgacggctccttcttcctctatagcgacctcaccgtggacaa gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgagg ctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgga ggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcgg tggaagcgcgcgcaacggagaccactgtccgctcgggcccgggcgttgct gccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgat tgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtg cccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcc tgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgcc agctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgct ccagacctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:23).

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:24.

II.A.3 DhMonoFc-(G₄S)₄-GDF15(H6D)

The designation “DhMonoFc-(G4S)4-GDF15(H6D)” in the instant disclosure refers to fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc domain via a polypeptide linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc domain. The GDF15(H6D) variant is a naturally-occurring human GDF15 variant.

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two DhMonoFc domains (one each monomer) comprising the sequence of SEQ ID NO:22, (b) two GDF15(H6D) polypeptides (one each monomer) comprising the sequence:

ARNGDDCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS

QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT YDDLLAKDCHCI (SEQ ID NO:25), and (c) two polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO: 18 each linking the N-terminus of the GDF15 polypeptide to the C-terminus of the

DhMonoFc domain.

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In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 5 PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSARNGDDCPLGPGRC CRLHTVRAS LEDLGWADWVL S PREVQVTMCIGAC PSQFRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID

NO :27), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgaccaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcg gtggaagcgcgcgcaacggagacgactgtccgctcgggcccgggcgttgc tgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccga ttgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgt gcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagc ctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgc cagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgc tccagacctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO :2 6) .

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:27.

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II.B, HemiFc

The designations “Hemi-” or “HemiFc domain’’ in the instant disclosure refer to a polypeptide chain comprising a first Fc domain linked, directly or via a polypeptide linker, to a second Fc domain. In one embodiment, the first Fc domain and the second Fc domain have the same sequence. In another embodiment, the first Fc domain and second Fc domain have different sequences. Typically, the first and second Fc domains are covalently associated via disulfide bonds between their respective hinge regions.

The C-terminal lysine (K447) optionally may be deleted in the first Fc domain, the 10 second Fc domain, or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

A fusion protein is provided comprising a HemiFc domain and a GDF15 region.

Typically, the N-terminus of the GDF15 region is linked, directly or via a polypeptide linker, to the C-terminus of the HemiFc domain. However, in some embodiments, the N-terminus of the HemiFc domain is linked, directly or via a polypeptide linker, to the C-terminus of the GDF15 region.

In certain embodiments, a dimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions. In some embodiments the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

See Figure 3 for a graphic depiction of an embodiment of a homodimer of two GGG-Fc(G4S)4-Fc-S(G₄S)4-GDF15 fusion proteins.

GGGFc-(G₄S)₄-Fc-S(G₄S)₄-GDF1 5

The designation “GGGFc-(G4S)4-Fc-S(G₄S)4-GDF15” in the instant disclosure refers 25 to a fusion protein comprising a GDF15 polypeptide linked to HemiFc domain via a first polypeptide linker comprising the sequence of SEQ ID NO:30, that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HemiFc domain. The HemiFc domain comprises a first Fc domain linked to a second Fc domain via a polypeptide linker comprising the sequence of SEQ ID NO: 18, that connects the N-terminus of the first Fc domain to the

C-terminus of the second Fc domain (which has three glycine residues added to its Nterminus).

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two second Fc domains (one each monomer) comprising the sequence (part of the hinge region in parentheses):

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GGG (ERKSSVECPPCP) APPVAGPSVFLFPPKPKDTLMISRTPEVTCWV DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWL NGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:28), (b) two first Fc domains (one each monomer) comprising the sequence (part of the hinge region in parentheses):

(ERKSSVECPPCP)APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGK

EYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:29).

(c) two second polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO: 18 linking the N-terminus of the first Fc domain to the C-terminus of the second

Fc domain, (d) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12, and (e) two first polypeptide linkers (one each monomer) comprising sequence:

SGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:30) linking the N-terminus of a GDF15 polypeptide to the C-terminus of a first Fc domain.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (part of the hinge region in parentheses; linker sequences double underlined):

GGG (ERKSSVECPPCP) APPVAGPSVFLFPPKPKDTLMISRTPEVTCWV DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWL

NGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGG GS (ERKSSVECPPCP) APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLN

GKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSGGG Q^ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGAC

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PSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSL QTYDDLLAKDCHCI (SEQ ID NO:32), which is encoded by the nucleic acid sequence:

ggaggtggagagcgcaaatcttctgtcgagtgcccaccgtgcccagcacc 5 acctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtg agccacgaagaccccgaggtccagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaaaccacgggaggagcagttcaacagcacgt tccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggc aaggagtacaagtgcaaggtctccaacaaaggcctcccagcccccatcga gaaaaccatctccaaaaccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacacctcccatgctggact ccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggaggtggcg gtagcggtggcggaggttcaggtggcggcggaagcggtggaggaggttca gagcggaaatccagcgttgaatgtcctccgtgccctgctccacccgtcgc ggggcctagtgtcttccttttccctccaaaaccaaaggatacactgatga tcagccggacccccgaggttacgtgcgtcgtcgtcgatgtctcccacgag gatccagaggtccaattcaactggtacgtggacggggtcgaggtgcataa tgcaaagacaaagccacgggaagagcagtttaactctactttccgcgtgg tttctgtgctgaccgtggtgcaccaagattggctcaacggcaaggagtac aagtgcaaggtaagcaataaggggctccctgcccccattgagaagactat ctccaagacaaagggacagccacgcgagccacaagtctatacactccccc cttcccgcgaagaaatgaccaagaatcaggttagcctgacatgcttggtt aagggtttctacccctctgacatagccgtggagtgggagagcaatggaca accagagaacaactacaagaccaccccacccatgctggatagcgacggtt cattctttctgtatagtaagcttaccgtggacaagtcccggtggcaacaa ggaaatgtcttttcatgctctgtgatgcacgaggccttgcataatcacta tactcagaagagcttgagcctcagccccggatctggaggtggcggatccg ggggcggtggaagcggaggtggtggatcgggaggcggtggaagcgcgcgc aacggcgaccactgtccgctcgggcccggacgttgctgccgtctgcacac ggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgc cacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttc

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As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:32.

II.C. DhHemiFc

The designations “DhHemi-” or “DhHemiFc domain’’ in the instant disclosure refer to a polypeptide chain comprising a first Fc domain from which all or part of the hinge region has been removed (“DhFc” domain) linked, directly or via a polypeptide linker, to a second DhFc domain. In particular embodiments, the N-terminal 12 amino acids in the hinge region are removed, e.g., ERKSSVECPPCP (SEQ ID NO:15). In one embodiment, the first DhFc domain and the second DhFc domain have the same sequence. In another embodiment, the first DhFc domain and the second DhFc domain have different sequences.

A fusion protein is provided comprising a DhHemiFc domain and a GDF 15 region.

Typically, the N-terminus of the GDF 15 region is linked, directly or via a polypeptide linker, to the C-terminus of the DhHemiFc domain. However, in some embodiments, the N-terminus of the DhHemiFc domain is linked, directly or via a polypeptide linker, to the C-terminus of the GDF 15 region.

In certain embodiments, a dimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF 15 regions. In some embodiments the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

GGGDhFc-(G₄S)₅-DhFc-S(G₄S)₄-GDF15

The designation “GGGDhFc-(G4S)₅-DliFc-S(G4S)4-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF 15 polypeptide linked to a DhHemiFc domain via a first polypeptide linker comprising the sequence of SEQ ID NO:30, that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HemiFc domain. The HemiFc domain comprises a first DhFc domain linked to a second DhFc domain via a polypeptide linker comprising the sequence of SEQ ID NO:34, that connects the N-terminus of the first DhFc domain to the C-terminus of the second DhFc domain (which has three glycine residues added to its N-terminus).

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

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GGGAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWY

VDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGKEYKCKVSNKGL

PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG (SEQ ID NO:33), (b) two first DhFc domains (one each monomer) comprising the sequence:

APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWYVDG

VEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAP

IEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPG (SEQ ID NO:35), (c) two second polypeptide linkers (one each monomer) comprising the sequence:

GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:34) linking the N-terminus of the first DhFc domain to the C-terminus of the second DhFc domain, (d) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12, and (e) two first polypeptide linkers (one each monomer) comprising the sequence of

SEQ ID NO:30 linking the N-terminus of a GDF15 polypeptide to the C-terminus of a first

DhFc domain.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker sequences double underlined):

GGGAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWY

VDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGKEYKCKVSNKGL PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKS L S L SPGGGGGSGGGGSGGGGSGGGGSGGGGSAPPVAGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAK

TKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISK TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

KS L S L S PGSGGGGSGGGGSGGGGSGGGGSARNGDHC PLGPGRCCRLHTVR

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ASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPD TVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:37), which is encoded by the nucleic acid sequence:

ggcggtggagctccgccggtggctggaccctcagtgttcctctttccacc 5 gaagccgaaggacacccttatgattagccggaccccagaggtcacttgcg tcgtcgtggacgtgtcccatgaggatcccgaagtgcagtttaactggtat gtggacggagtggaggtccataacgccaagaccaagccaagggaagaaca gttcaatagcaccttccgggtggtgtccgtgctcaccgtggtgcatcaag actggctgaatggcaaagagtacaaatgtaaggtgtcaaacaaggggctc ccagcccctattgaaaagaccatctcaaagactaagggacagccacgcga acctcaagtgtataccctcccgccttcacgcgaagaaatgactaagaatc aggtcagccttacttgtctggtcaagggcttctacccgagcgacattgca gtcgaatgggagagcaatggtcagccagagaataactacaagaccactcc tcccatgcttgatagcgatggaagctttttcctttacagcaagcttactg tggataagtctcgctggcaacagggaaatgtgttcagetgttcagtgatg catgaagcactccacaatcattacacccagaagtcactcagcctctcacc cggaggaggaggcggttctggtggaggagggtctggaggtggagggagcg gcggaggcgggtctggcggtggtgggtctgagaggaagtcatcagtggaa tgcccaccatgccctgctcctcccgtggccggtccgagcgtgtttctctt cccacctaagcccaaggacactctgatgatctcacggactccggaagtga cttgtgtggtggtggacgtgtctcatgaggaccctgaagtgcagttcaac tggtacgtggacggcgtggaggtgcacaatgctaagaccaagcctagaga ggaacagttcaattccacctttcgcgtggtgagcgtcctgaccgtcgtgc accaggactggcttaacggaaaggaatacaagtgcaaggtgtccaacaaa ggccttccagctcccattgagaaaaccatctctaaaactaagggtcaacc aagggaaccccaagtctacaccctccctccgtctagagaagagatgacca aaaaccaggtgtccctgacctgtctggtgaagggattttacccctcagac atcgccgtggagtgggaaagcaacggacagcccgaaaacaactataagac tacccctcctatgctggactcagacggatctttcttcctctatagcaagc tcactgtggacaaatccagatggcaacaagggaatgtgttctcatgcagc gtgatgcacgaggctcttcacaaccactatacccagaagagcctgtctct ttcacctggttccggaggtggtgggagcggagggggtggatcaggtggtg gagggtccggaggcggaggatccgcacggaatggcgaccactgtccactg ggacccggaagatgttgtcgcctccacaccgtgagggcctctctggagga ccttggctgggccgactgggtcctgtcacctcgggaggtccaagtcaeca tgtgtatcggagcctgccccagccaattcagagcagcaaatatgcacgca

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As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers comprising the sequence of SEQ ID NO:37.

II.D. Knob/Hole

The designations “knob-” or “knobFc domain” in the instant disclosure refer to an Fc domain comprising a “knob” mutation. The designations “hole-” or “holeFc domain” in the instant disclosure refers to a native Fc or Fc variant comprising a “hole” mutation.

“Knobs” may be created by replacing small amino acid side chains with larger ones and “holes” may be created by replacing large amino acid side chains with smaller ones. See, e.g., Ridgway JBB 1996, Protein Eng. 9:617-621; Merchant AM 1998, Nature Biotech.

16:677-681.

In one embodiment, a “knobFc” domain is provided by introducing a threonine to tryptophan mutation (T366W) in the sequence of an Fc domain. In one embodiment, a “holeFc” domain is provided by introducing a threonine to serine mutation (T366S), a leucine to alanine mutation (L368A) and a tyrosine to valine mutation (Y407V) in the sequence of an

Fc domain.

The C-terminal lysine (K447) optionally may be deleted in the knobFc domain, the holeFc domain, or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

In one embodiment, a “DhknobFc” domain is provided by introducing a threonine to 25 tryptophan mutation (T366W) in the sequence of an Fc domain from which all or part of the hinge region has been removed. In one embodiment, a “DhholeFc” domain is provided by introducing a threonine to serine mutation (T366S), a leucine to alanine mutation (L368A) and a tyrosine to valine mutation (Y407V) in the sequence of an Fc domain from which all or part of the hinge region has been removed.

The C-terminal lysine (K447) optionally may be deleted in the DhknobFc, the

DhholeFc, or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

In some embodiments, a heterodimer is providing comprising (i) a first polypeptide chain comprising a GDF 15 region linked to a holeFc domain directly or via a polypeptide linker and (ii) a second polypeptide chain comprising a knobFc domain. In other embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a

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GDF15 region linked to a knobFc domain, directly or via a polypeptide linker and (ii) a second polypeptide chain comprising a holeFc domain.

In some embodiments, a heterodimer is providing comprising (i) a first polypeptide chain comprising a GDF15 region linked to a DhholeFc domain directly or via a polypeptide linker and (ii) a second polypeptide chain comprising a DhknobFc domain. In other embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a GDF15 region linked to a DhknobFc domain, directly or via a polypeptide linker and (ii) a second polypeptide chain comprising a DhholeFc domain.

In some embodiments, a tetramer is provided comprising two such heterodimers in 10 which the heterodimers are linked via an interchain disulfide bond between the GDF15 regions of their respective first polypeptide chains. See Figure 1 for a graphic depiction of an embodiment of a heterotetramer comprising two heterodimers, where each heterodimer comprises (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhknobFc domain via a polypeptide linker and (ii) a second polypeptide chain comprising a

DhholeFc domain.

DhknobFc-(G4S)4-GDFl5:DhholeFc

The designation “DhknobFc-(G4S)4-GDF15:DhholeFc” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhknobFc domain via a linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhknobFc domain and (ii) a polypeptide chain comprising a DhholeFc domain.

In certain embodiments, a tetramer is provided comprising a dimer of two DhknobFc(G4S)4-GDF15:DhholeFc heterodimers in which the first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhknobFc domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:16), (b) two DhholeFc domains (one each heterodimer) comprising the sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVE

WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:281), (c) two GDF 15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO: 18 each linking the N-terminus of a GDF 15 polypeptide to the C-terminus of a

DhknobFc domain via peptide bonds.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSARNGDHCPLGPGRC CRLHTVRAS LEDLGWADWVL S PREVQVTMCIGAC PSQFRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID

NO :20), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtca gcctgtggtgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctggactccgacggctccttcttcctctacagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcg

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:17), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtca gcctgagctgcgcggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctggactccgacggctccttcttcctcgtcagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa atga (SEQ ID NO:21)

As discussed above, in a specific embodiment, a tetramer is provided comprising two monomers having the sequence of SEQ ID NO:20 and two monomers having the sequence of SEQ ID NO: 17.

II.E, Charged pair (delHinge)

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The designation “CpmFc(+) domain” in the instant disclosure refers to an Fc domain comprising a “positive” charged pair mutation. The designation “CpmFc(-) domain” in the instant disclosure refers to an Fc domain comprising a “negative” charged pair mutation. Note that use of the terms “positive” and “negative” is for ease of reference (i.e., to describe the nature of the charged pair mutations in the Fc domains) and not to indicate that the overall sequence or construct necessarily has a positive or negative charge.

In one embodiment, a “positive” charged pair mutation is provided by introducing a glutamic acid to lysine mutation (E356K) and an aspartic acid to lysine mutation (D399K) in the sequence of an Fc domain. In one embodiment, a “negative” charged pair mutation is provided by introducing two lysine to aspartic acid mutations (K392D, K409D) in the sequence of an Fc domain.

When incubated together, the aspartate residues associate with the lysine residues through electrostatic force, facilitating formation of heterodimers between the CpmFc(+) domains and CpmFc(-) domains, and reducing or preventing formation of homodimers between the CpmFc(+) sequences or between CpmFc(-) sequences.

The C-terminal lysine (K447) optionally may be deleted in the CpmFc(+) domain, the CpmFc(-) domain, or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

In one embodiment, a “DhCpmFc(+)” domain is provided by introducing a glutamic 20 acid to lysine mutation (E356K) and an aspartic acid to lysine mutation (D399K) in the sequence of an Fc domain from which all or part of the hinge region has been removed. In one embodiment, a “DhCpmFc(-)” domain is provided by introducing two lysine to aspartic acid mutations (K392D, K409D) in the sequence of an Fc domain from which all or part of the hinge region has been removed.

When incubated together, the aspartate residues associate with the lysine residues through electrostatic force, facilitating formation of heterodimers between the DhCpmFc(+) domains and DhCpmFc(-) domains, and reducing or preventing formation of homodimers between the DhCpmFc(+) sequences or between DhCpmFc(-) sequences.

The C-terminal lysine (K447) optionally may be deleted in the DhCpmFc(+), the

DhCpmFc(-), or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

In some embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a GDF 15 region linked to a CpmFc(+) domain, and (ii) a second polypeptide chain comprising a CpmFc(-) domain. In some embodiments, the N-terminus of the GDF15 region is linked to the C-terminus of the CpmFc(+) domain, directly or via a polypeptide linker. In other embodiments, the N-terminus of the CpmFc(+) domain is linked to the C-terminus of the GDF 15 region, directly or via a polypeptide linker.

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In other embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a GDF15 region linked to a CpmFc(-) domain, and (ii) a second polypeptide chain comprising a CpmFc(+) domain. In some embodiments, the N-terminus of the GDF15 region is linked to the C-terminus of the CpmFc(-) domain, directly or via a polypeptide linker. In other embodiments, the N-terminus of the CpmFc(-) domain is linked to the Cterminus of the GDF15 region, directly or via a polypeptide linker.

In some embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a GDF15 region linked to a DhCpmFc(+) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(-) domain. In some embodiments, the N-terminus of the GDF15 region is linked to the C-terminus of the DhCpmFc(+) domain, directly or via a polypeptide linker. In other embodiments, the N-terminus of the DhCpmFc(+) domain is linked to the C-terminus of the GDF15 region, directly or via a polypeptide linker.

In other embodiments, a heterodimer is provided comprising (i) a first polypeptide chain comprising a GDF15 region linked to a DhCpmFc(-) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain. In some embodiments, the N-terminus of the GDF15 region is linked to the C-terminus of the DhCpmFc(-) domain, directly or via a polypeptide linker. In other embodiments, the N-terminus of the DhCpmFc(-) domain is linked to the C-terminus of the GDF15 region, directly or via a polypeptide linker.

In some embodiments, a tetramer is provided comprising a dimer of two such heterodimers in which the two first polypeptide chains of the heterodimers are linked via an interchain disulfide bond between their respective GDF15 regions. See Figure 4 for a graphic depiction of an embodiment of a tetramer comprising two heterodimers, where each heterodimer comprises (i) a first polypeptide chain comprising a GDF15 polypeptide linked via a polypeptide linker to a DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

ll.E. 1 DhCpmFc(+)-(lK)-GDF 15 :DhCpmFc(-)

The designation “DhCpmFc(+)-(lK)-GDF15:DhCpmFc(-)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhCpmFc(+) domain via a linker comprising the sequence of SEQ ID NO:40 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(+) domain and (ii) a second polypeptide chain comprising a DhCpmFc(-) domain.

In certain embodiments, a tetramer is provided comprising a dimer of two DhCpmFc(+)-(lK)-GDF15:DhCpmFc(-) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

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PCT/US2014/049254 (a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:38), (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:282), (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GSGSATGGSGSVASSGSGSATHL (SEQ ID NO:40) each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(+) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSP GGSGSATGGSGSVASSGSGSATHLARNGDHCPLGP

GRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQI KTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHC I (SEQ ID NO:42), which is encoded by the nucleic acid sequence:

gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac

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In a preferred embodiment, the second polypeptide chain and comprises the amino acid sequence

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO :39), which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaacagtataa cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtataccctgccgccgagccgcgaagaaatgaccaaaaaccaggtga

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:42 and two polypeptide chains comprising the sequence of SEQ ID NO:39.

11.E.2 DhCpmFc(j-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided comprising a dimer of two DhCpmFc(-)-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 25 PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:283), (b) two DhCpmFc(-) domains (one each heterodimer) comprising the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:48),

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In a preferred embodiment, the first polypeptide chain comprises the amino acid 5 sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:50), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcaacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:49).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK(SEQ ID NO:47), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctgaagtccgacggctccttcttcctctatagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa atga (SEQ ID NO:51).

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:50 and two polypeptide chains having the sequence of SEQ ID NO:47.

II.E.3 DhCpmFc(-)-GDF15(N3D):DhCpmFc(+)

The designation “DhCpmFc(-)-GDF15(N3D):DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a naturallyoccurring variant of a GDF15 having an asparagine to aspartic acid mutation (N3D) (“GDF15(N3D)”), the N-terminus of which is linked directly to the C-terminus of a

DhCpmFc(-) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain. The N3D mutation may reduce deamidation induced heterogeneity.

In certain embodiments, a tetramer is provided comprising a dimer of two DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

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More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) having the sequence of SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) having the sequence of SEQ ID

NO:48, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence:

ARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT YDDLLAKDCHCI (SEQ ID NO:52).

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:54), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having 10 the sequence of SEQ ID NO:54 and two polypeptide chains having the sequence of SEQ ID

NO:47.

11.E.4 DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+)

The designation “DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+)” in the instant 15 disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a variant of GDF15 in which the first three amino acids are deleted (“GDF15(Ndel3”), the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain. The Ndel3 variant may reduce N3 deamidation and subsequent D3 isomerization induced heterogeneity.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) having the sequence of SEQ

ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) having the sequence of SEQ ID NO:48, and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) having the sequence:

GDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDD LLAKDCHCI (SEQ ID NO:55).

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:57), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc 10 caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:56).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provide comprising two polypeptide chains having the sequence of SEQ ID NO:57 and two polypeptide chains having the sequence of SEQ ID NO:47.

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II.F.5 DhCpmFc(-)-G₄-GDF15(N3D):DhCpmFc(+)

The designation “DhCpmFc(-)-G4-GDF15(N3D):DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:58 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)-G4-GDF15(N3D):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) having the sequence of SEQ

ID NO:283, (b) two DhCpmFc(+) domains (one each heterodimer) having the sequence of SEQ

ID NO:48, (c) two a GDF15(N3D) polypeptides (one each heterodimer) having the sequence of SEQ ID NO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGG (SEQ ID NO :58) each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-) domain via peptide bonds.

In a preferred embodiment, the first polypeptide comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGARDGDHCPLGPGRCCRLHTVRASLEDLGWA 30 DWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP

ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:60), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg

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PCT/US2014/049254 tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggagcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggcc gattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgc gtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacga gcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgccc gccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:59).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID

NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:60 and two polypeptide chains having the sequence of SEQ ID NO:47.

ILE.6 DhCpmFc(-)-G₄S-GDFL5:DhCpmFc(+)

The designation “DhCpmFc(-)-G4S-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF 15 polypeptide linked to a DhCpmFc(-) domain via a polypeptide linker comprising the sequence of SEQ ID NO:61 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)-G₄S-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

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More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of 5 SEQ ID NO:48, (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGS (SEQ ID NO:61) each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(-) domain via peptide bonds.

In a preferred embodiment, the first polypeptide comprises the amino acid sequence (linker double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSARNGDHCPLGPGRCCRLHTVRASLEDLGW

ADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCV

PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:63), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg

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In a preferred embodiment, the second polypeptide comprises the amino acid 10 sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID

NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:63 and two polypeptide chains having the sequence of SEQ ID NO:47.

ll.E. 7 DhCpmFc(-)-(G₄S)2-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-(G4S)2-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhCpmFc(-) domain via a polypeptide linker comprising the sequence of SEQ ID NO:64 that connects N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)-(G4S)2-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:48, (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGSGGGGS (SEQ ID NO:64),

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP

APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:66), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcggtggaagcgcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:65).

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains 5 comprising the sequence of SEQ ID NO:66 and two polypeptide chains comprising the sequence of SEQ ID NO:47.

II.E.8 DhCpmFc(-)-(G₄S)₂-GDF15(N3D):DhCpmFc(+)

The designation “DhCpmFc(-)-(G4S)2-GDF15(N3D):DhCpmFc(+)” in the instant 10 disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:64 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a

DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-(G4S)2-GDF15(N3D):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:64, each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid 30 sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSARDGDHCPLGPGRCCRLHTVRASL

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EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP

APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:68), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc 5 caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcggtggaagcgcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:67).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:68 and two polypeptide chains having the sequence of SEQ ID

NO:47.

11.E.9 DhCpmFc(-)-G₄P-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-(G4P)-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF 15

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In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-(G4P)-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ

ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGP (SEQ ID NO:69), each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGPARNGDHCPLGPGRCCRLHTVRASLEDLGW

ADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:71), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc

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PCT/US2014/049254 tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacccgcgcgcaacggagaccactgtccgctcgggcccgggc gttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgg gccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcgg cgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaaga cgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtg cccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggt gtcgctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO :70) .

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:71 and two polypeptide chains having the sequence of SEQ ID NO:47.

II.E.10 DhCpmFc(-)-(G₄P)₂-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-(G4P)2-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:72 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second v comprising a DhCpmFc(+) sequence.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-(G4P)2-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:283,

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PCT/US2014/049254 (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF 15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGPGGGGP(SEQ ID NO:72), each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTOKSLSLSPGGGGGPGGGGPARNGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:74), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacctggaggcggtggaccagcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt

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PCT/US2014/049254 gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcatatga (SEQ ID NO:73).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having 10 the sequence of SEQ ID NO:74 and two polypeptide chains comprising the sequence of SEQ

ID NO:47.

II.E. 11 DhCpmFc(-)-G₄Q-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-G4Q-GDF15:DhCpmFc(+)” in the instant disclosure 15 refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:75 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the

DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two 20 DhCpmFc(-)-G4Q-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) chains (one each heterodimer) comprising the sequence of SEQ

IDNO:283, (b) two DhCpmFc(-) chains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGQ (SEQ ID NO:75) each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid 35 sequence (linker sequence double underlined):

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGQARNGDHCPLGPGRCCRLHTVRASLEDLGW ADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:77), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc 10 caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcactgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacaggcgcgcaacggagaccactgtccgctcgggcccgggc gttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgg gccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcgg cgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaaga cgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtg cccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggt gtcgctccagacctatgatgacttgttagccaaagactgccactgcatat ga (SEQ ID NO:76).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:77 and two polypeptide chains having the sequence of SEQ ID

NO:47.

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PCT/US2014/049254 ll.E. 12 DhCpmFc(-)-(G₄Q)₂-GDF15:DhCpmFc(+)

The designation “DhCpmFc(-)-(G4Q)₂-GDF15:DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a 5 GDF15 polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of

SEQ ID NO:78 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-(G4Q)₂-GDF15:DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQIDNO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence:

GGGGQGGGGQ (SEQ ID NO:78) each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGQGGGGQARNGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:80), which is encoded by the nucleic acid sequence:

WO 2015/017710

PCT/US2014/049254 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacaggcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcatatga (SEQ ID NO:79).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID

NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having the sequence of SEQ ID NO:80 and two polypeptide chains having the sequence of SEQ ID NO:47.

ll.E. 13 DhCpmFc(-)-(G₄Q)2-GDF15(N3D):DhCpmFc(+)

The designation “DhCpmFc(-)-(G4Q)2-GDF15(N3D):DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:78 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a

DhCpmFc(+) domain.

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In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)-(G4Q)2-GDF15(N3D):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:78 each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGQGGGGQARDGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:82), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca

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PCT/US2014/049254 agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacaggcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:81).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having 15 the sequence of SEQ ID NO:82 and two polypeptide chains having the sequence of SEQ ID

NO:47.

II.E. 14 DhCpmFc(-)-(G₄Q)_rGDF15(Ndel3):DhCpmFc(+)

The designation “DhCpmFc(-)-(G4Q)2-GDF15(Ndel3):DhCpmFc(+)” in the instant 20 disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide linked to a DhCpmFc(-) domain via a linker comprising the sequence of SEQ ID NO:78 that connects the N-terminus of the GDF15(Ndel3) polypeptide to the C-terminus of the DhCpmFc(-) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)-(G4Q)2-GDF15(Ndel3):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:283, (b) two DhCpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:48, (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55, and

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PCT/US2014/049254 (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:78 each linking the N-terminus of a GDF15(Ndel3) polypeptide to the C-terminus of a DhCpmFc(-) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid 5 sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTOKSLSLSPGGGGGOGGGGOGDHCPLGPGRCCRLHTVRASLEDL GWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:84), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacagggagaccactgtccgctcgggc ccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctg ggctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtg catcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcaga tcaagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgc tgcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacac cggggtgtcgctccagacctatgatgacttgttagccaaagactgccact gcata (SEQ ID NO:83).

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:47, which is encoded by the nucleic acid sequence of SEQ ID NO:51.

As discussed above, a tetramer is provided comprising two polypeptide chains having 5 the sequence of SEQ ID NO:84 and two polypeptide chains having the sequence of SEQ ID

NO:47.

II.F. Charged pair (delHinge) Cysteine Clamp

A “cysteine clamp” mutation may be introduced into a Fc domain, such as a 10 CpmFc(+) domain, a CpmFc(-) domain, a DhCpmFc(+) domain, or a DhCpmFc(-) domain. A “cysteine clamp” mutation typically involves the introduction of a cysteine into the CH3 domain of an Fc domain at a specific location through mutation so that when incubated with another Fc domain, also having a cysteine introduced into the CH3 domain at a specific location through mutation, a disulfide bond (cysteine clamp) may be formed between the two

Fc domains (e.g., between a CpmFc(+) domain having a “cysteine clamp” mutation and a CpmFc(-) domain having a “cysteine clamp” mutation or between a DhCpmFc(+) domain having a “cysteine clamp” mutation and a DhCpmFc(-) domain having a “cysteine clamp” mutation). An Fc domain may contain one or more such cysteine clamp mutations.

In one embodiment, a cysteine clamp is provided by introducing a serine to cysteine mutation (S354C) into a first Fc domain and a tyrosine to cysteine mutation (Y349C) into a second Fc domain.

The designation “DhCpmFc(-)(S354C)” domain in the instant disclosure refers to an DhCpmFc(-) domain comprising a serine to cysteine mutation (S354C). The designation “DhCpmFc(+)(S354C)” domain in the instant disclosure refers to an DhCpmFc(+) domain comprising a serine to cysteine mutation (S354C). The designation “DhCpmFc(-)(Y349C)” domain in the instant disclosure refers to an DhCpmFc(-) domain comprising a serine to cysteine mutation (Y349C). The designation “DhCpmFc(+)(Y349C)” domain in the instant disclosure refers to an DhCpmFc(+) domain comprising a serine to cysteine mutation (Y349C).

The designation “CpmFc(-)(S354C)” domain in the instant disclosure refers to an

CpmFc(-) domain comprising a serine to cysteine mutation (S354C). The designation “CpmFc(+)(S354C)” domain in the instant disclosure refers to an CpmFc(+) domain comprising a serine to cysteine mutation (S354C). The designation “CpmFc(-)(Y349C)” domain in the instant disclosure refers to an CpmFc(-) domain comprising a serine to cysteine mutation (Y349C). The designation “CpmFc(+)(Y349C)” domain in the instant disclosure refers to an CpmFc(+) domain comprising a serine to cysteine mutation (Y349C).

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In another embodiment, a cysteine clamp is provided by introducing a leucine to cysteine mutation (L351C) into both a first and Fc domain.

The designation “DhCpmFc(-)(L351C)” domain in the instant disclosure refers to an DhCpmFc(-) domain comprising a serine to cysteine mutation (L351C). The designation “DhCpmFc(+)(L351C)” domain in the instant disclosure refers to an DhCpmFc(+) domain comprising a serine to cysteine mutation (L351C).

The designation “CpmFc(-)(L351C)” domain in the instant disclosure refers to an CpmFc(-) domain comprising a serine to cysteine mutation (L351C). The designation “CpmFc(+)(L351C)” domain in the instant disclosure refers to an CpmFc(+) domain comprising a serine to cysteine mutation (L351C).

The C-terminal lysine (K447) optionally may be deleted in the CpmFc(+) domain, the CpmFc(-) domain, or both. This may be advantageous, for example, when a peptide is fused at the C-terminus to reduce proteolysis of the fusion protein.

In some embodiments a heterodimer is provided comprises (i) a first polypeptide 15 chain comprising a GDF 15 region linked to a CpmFc(+) domain comprising a cysteine clamp mutation and (ii) a second polypeptide chain comprising a CpmFc(-) domain comprising a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF 15 region is linked to the C-terminus of the CpmFc(+) domain comprising a cysteine clamp mutation, directly or via a polypeptide linker. In other embodiments, the N-terminus of the CpmFc(+) domain comprising a cysteine clamp mutation is linked to the C-terminus of the GDF 15 region, directly or via a polypeptide linker.

In some embodiments a heterodimer is provided comprises (i) a first polypeptide chain comprising a GDF 15 region linked to a CpmFc(-) domain comprising a cysteine clamp mutation and (ii) a second polypeptide chain comprising a CpmFc(+) domain comprising a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF 15 region is linked to the C-terminus of the CpmFc(-) domain comprising a cysteine clamp mutation, directly or via a polypeptide linker. In other embodiments, the N-terminus of the CpmFc(-) domain comprising a cysteine clamp mutation is linked to the C-terminus of the GDF 15 region, directly or via a polypeptide linker.

In some embodiments a heterodimer is provided comprises (i) a first polypeptide chain comprising a GDF 15 region linked to a DhCpmFc(+) domain comprising a cysteine clamp mutation and (ii) a second polypeptide chain comprising a DhCpmFc(-) domain comprising a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF 15 region is linked to the C-terminus of the DhCpmFc(+) domain comprising a cysteine clamp mutation, directly or via a polypeptide linker. In other embodiments, the N-terminus of the DhCpmFc(+) domain comprising a cysteine clamp mutation is linked to the C-terminus of the GDF 15 region, directly or via a polypeptide linker.

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In some embodiments a heterodimer is provided comprises (i) a first polypeptide chain comprising a GDF15 region linked to a DhCpmFc(-) domain comprising a cysteine clamp mutation and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain comprising a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF15 region is linked to the C-terminus of the DhCpmFc(-) domain comprising a cysteine clamp mutation, directly or via a polypeptide linker. In other embodiments, the N-terminus of the DhCpmFc(-) domain comprising a cysteine clamp mutation is linked to the C-terminus of the GDF15 region, directly or via a polypeptide linker.

In some embodiments, a tetramer is provided comprising a dimer of two such 10 heterodimers in which the two first polypeptide chains of the heterodimers are linked via an interchain disulfide bond between their respective GDF15 regions. See Figure 5 for a graphic depiction of an embodiment of a tetramer comprising two heterodimers, where each heterodimer comprises (i) a first polypeptide chain comprising a GDF15 polypeptide linked via a polypeptide linker to a DhCpmFc(+)(L351C) domain and (ii) a second polypeptide chain comprising a DhCpmFc(-)(L351C) domain.

ILF. 1 DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc(-)(Y349C)

The designation “DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc(-)(Y349C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a

GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(+)(S354C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(-)(Y349C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C354 of the first polypeptide chain and C349 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc(-)(Y349C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO :85),

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PCT/US2014/049254 (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 5 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:284), and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:88), which is encoded by the nucleic acid sequence:

gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacaa tagcacctaccgcgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcactgtccctgtcacctggcgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc

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PCT/US2014/049254 acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:87).

In a preferred embodiment, the second polypeptide chain and comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:86), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa a (SEQ ID NO:89).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:88 and two polypeptide chains comprising the sequence of SEQ ID NO: 86.

II.F.2 DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C)

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The designation “DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a

GDF15 polypeptide, the N-terminus of which is linked directly to the C-terminus of a

DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a

DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:285), (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:91), and (c) two GDF15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

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WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:93), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcaacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:92).

In a preferred embodiment, the second polypeptide chain comprises the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:90), which is encoded by the nucleic acid sequence:

gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg

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PCT/US2014/049254 tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacaa tagcacctaccgcgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcactgtccctgtctccgggtaa a (SEQ ID NO:94).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:93 and two polypeptide chains comprising the sequence of SEQ ID NO:90.

11.F.3 DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C)

The designation “DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C)’’ in the instant disclosure refers to heterodimer comprising (i) a first polypeptide chain comprising a

GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(Y349C) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions. An N3D mutation in GDF15 sequence may be introduced, e.g., to eliminate heterogeneity caused by N deamidation.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:285, (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:91, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 5 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:96), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:95).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:90, which is encoded by the nucleic acid sequence of SEQ ID NO:94.

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:96 and two polypeptide chains comprising the sequence of SEQ ID NO:90.

11.F.4 DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C)

The designation “DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a

DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions. Deletion of the N-terminal 3 amino acids (Ndel3) in GDF 15 sequence may be introduced, e.g., to eliminate heterogeneity caused by deamidation of asparagines or isomerization of aspartic acid.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) of comprising the sequence of SEQ ID NO:285, (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:91, and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:98), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:97).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:90, which is encoded by the nucleic acid sequence of SEQ ID NO:94.

As discussed above, a tetramer is provided comprising two polypeptide chains 25 comprising the sequence of SEQ ID NO:98 and two polypeptide chains comprising the sequence of SEQ ID NO:90.

II.F.5 DhCpmFc(-)(Y349C)-G₄-GDF15(N3D):DhCpmFc(+)(S354C)

The designation “DhCpmFc(-)(Y349C)-G4-GDF15(N3D):DhCpmFc(+)(S354C)” in 30 the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-)(Y349C) domain via a linker comprising the sequence of SEQ ID NO:58 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-)(Y349C) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

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In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(Y349C)-G4-GDF15(N3D):DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) of comprising the sequence of SEQ ID NO:285, (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:91, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:58 each linking the N -terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-)(Y349C) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGARDGDHCPLGPGRCCRLHTVRASLEDLGWA

DWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:100), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca

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PCT/US2014/049254 agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg tggaggtggtgcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggcc gattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgc gtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacga gcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgccc gccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:99).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:90, which is encoded by the nucleic acid sequence of SEQ ID NO:94.

As discussed above, in a specific embodiment, a heterotetramer is provided comprising two monomers having the sequence of SEQ ID NO: 100 and two monomers having the sequence of SEQ ID NO:90.

ll.F. 6 DhCpmFc(-)(Y349C)-(G₄S)₂-GDF15(N3D):DhCpmFc(+)(S354C)

The designation “DhCpmFc(-)(Y349C)-(G4S)2-GDF15(N3D):DhCpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-)(Y349C) domain via a linker comprising the sequence of SEQ ID NO:64 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(Y349C)-(G₄S)2-GDF15(N3D):DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) of comprising the sequence of SEQ ID NO:285, (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:91, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52, and

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PCT/US2014/049254 (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:64 each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-)(Y349C) domain via a peptide bond.

In a preferred embodiment, the first polypeptide comprises the amino acid sequence 5 (linker sequence double underlined):

APEIIGGPSVFIFPPKPKDTIMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTOKSLSLSPGGGGGSGGGGSARDGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:102), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcggtggaagcgcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NQ:101).

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:90, which is encoded by the nucleic acid sequence of SEQ ID NO:94.

As discussed above, in a specific embodiment, a heterotetramer is provided 5 comprising two monomers having the sequence of SEQ ID NO: 102 and two monomers having the sequence of SEQ ID NO:90.

ll.F. 7 DhCpmFc(-)(Y349C)-(G₄Q)₂-GDF15(N3D):DhCpmFc(+)(S354C)

The designation “DhCpmFc(-)(Y349C)-(G₄Q)2-GDF15(N3D):DhCpmFc(+)(S354C)” 10 in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-)(Y349C) domain via a linker comprising the sequence of SEQ ID NO:78 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(Y349C)-(G₄Q)2-GDF15(N3D):DhCpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (one each heterodimer) of comprising the sequence of SEQ ID NO:285, (b) two DhCpmFc(-)(Y349C) domains (one each heterodimer) comprising the 25 sequence of SEQ ID NO:91, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:78 each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a

DhCpmFc(-)(Y349C) domain via a peptide bond.

In a preferred embodiment, the first polypeptide comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 35 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

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ALHNHYTQKSLSLSPGGGGGQGGGGQARDGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:104), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacaggcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:103).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:90, which is encoded by the nucleic acid sequence of SEQ ID NO:94.

As discussed above, in a specific embodiment, a heterotetramer is provided 30 comprising two monomers having the sequence of SEQ ID NO: 104 and two monomers having the sequence of SEQ ID NO:90.

II.F.8. DhCpmFc(-)(L351C)-(G₄S)₂-GDF15:DhCpmFc(+)(L351C)

The designation “DhCpmFc(-)(L351C)-(G4S)₂-GDF15:DhCpmFc(+)(L351C)” in the 35 instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a

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GDF15 polypeptide linked to a DhCpmFc(-)(L351C) domain via a linker comprising the sequence of SEQ ID NO:64 that connects the N-terminus of the GDF15 polypeptide to the

C-terminus of the DhCpmFc(-)(L351C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(L351C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(L351C)-(G4S)₂-GDF15:DhCpmFc(+)(L351C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(L351C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:286), (b) two DhCpmFc(-)(L351C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:106), (c) two GDF 15 polypeptide chains (one each heterodimer) comprising the sequence of SEQ ID NO: 12, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:64 each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a

DhCpmFc(-)(L351C) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (linker sequence double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

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PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP 5 APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:108), which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaacagtataa cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgagccgcgaagaaatgaccaaaaaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactatgataccaccccgccggt gctggatagcgatggcagcttttttctgtatagcgatctgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcgtgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgg cggcggcggcagcggcggcggcggcagcgcgcgcaacggcgatcattgcc cgctgggcccgggccgctgctgccgcctgcataccgtgcgcgcgagcctg gaagatctgggctgggcggattgggtgctgagcccgcgcgaagtgcaggt gaccatgtgcattggcgcgtgcccgagccagtttcgcgcggcgaacatgc atgcgcagattaaaaccagcctgcatcgcctgaaaccggataccgtgccg gcgccgtgctgcgtgccggcgagctataacccgatggtgctgattcagaa aaccgataccggcgtgagcctgcagacctatgatgatctgctggcgaaag attgccattgcatt (SEQ ID NO:107).

In a preferred embodiment, the second polypeptide chain and comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO :105),

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PCT/US2014/049254 which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacacctgtcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa a (SEQ ID NO:109) .

As discussed above, in a specific embodiment, a heterotetramer is provided comprising two monomers having the sequence of SEQ ID NO: 108 and two monomers having the sequence of SEQ ID NO: 105.

II.G. HSA

The designations “HSA” or “human serum albumin” in the instant disclosure refer to a fusion protein comprising a GDF15 region linked, directly or via a polypeptide linker, to a human serum albumin (HSA) polypeptide. In some embodiments, the fusion protein comprises two or more HSA polypeptides.

Typically, the N-terminus of the GDF15 region is linked, directly or via a polypeptide linker, to the C-terminus of the HSA polypeptide. However, in some embodiments, the Nterminus of the HSA polypeptide is linked, directly or via a polypeptide linker, to the Cterminus of the GDF15 region.

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via an interchain disulfide bond between their respective GDF15 regions. See Figure 6 for a graphic depiction of an embodiment of such a homodimer. Alternatively, a heterodimer is provided comprising one such fusion protein and a GDF15 polypeptide or GDF mutant polypeptide, linked via an interchain disulfide bond between the GDF15 region of the fusion protein and the GDF 15 polypeptide or mutant polypeptide.

II.G.I HSA-(G4S)4-GDF15:GDF15 heterodimer

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The designation “HSA-(G4S)4-GDF15:GDF15” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide, and (ii) a second polypeptide chain comprising a GDF15 polypeptide.

Typically, the first and second polypeptide chains are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the heterodimer comprises:

(a) one HSA polypeptide (first monomer) comprising the sequence:

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL

LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE

DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK

EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD FAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL(SEQ ID NO:110), and (b) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12, and (c) one polypeptide linker (first monomer) comprising the sequence of SEQ ID

NO: 18 linking the N-terminus of a GDF15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

In a preferred embodiment, the first polypeptide comprises the amino acid sequence (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL

LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

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KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE

DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK

EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD

FAAFVEKCCKADDKETCFAEEGKKLVAASOAALGLGGGGSGGGGSGGGGS

GGGGSARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVOVTMCI

GACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTG VSLQTYDDLLAKDCHCI (SEQ ID NO :112), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa

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PCT/US2014/049254 gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggtggtggatccggaggcggtggaagcggaggtggtggatct ggaggcggtggaagcgcgcgcaacggagaccactgtccgctcgggcccgg gcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggct gggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatc ggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaa gacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcg tgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccggg gtgtcgctccagacctatgatgacttgttagccaaagactgccactgcat atga (SEQ ID NO:111).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12, which is encoded by the nucleic acid sequence of SEQ ID

NOTl.

As discussed above, a heterodimer is provided comprising a first polypeptide chain having the sequence of SEQ ID NO:112 and a second polypeptide chain having the sequence of SEQ ID NO: 12.

11.G.2 HSA-(G₄S)₄-GDF15

The designation “HSA-(G4S)4-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF 15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the GDF 15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSA-(G₄S)₄GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID

ΝΟΤΙΟ;

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PCT/US2014/049254 (b) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12, and (c) two polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO:18 each linking the N-terminus of a GDF15 polypeptide to the C-terminus of an HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence of SEQ ID NO: 112, which is encoded by the nucleic acid sequence of SEQ ID NO: 111.

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO:112.

II.G.3 HSA-GSPAPAPGS-GDF15

The designation “HSA-(GSPAPAPGS)-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 113 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSA(GSPAPAPGS)-GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID

NO: 110;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GSPAPAPGS (SEQ ID NO:113) each linking the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL

LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

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KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE

DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK

EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD

FAAFVEKCCKADDKETCFAEEGKKLVAASQAALGLGSPAPAPGSARNGDH CPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAAN MHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLA KDCHCI (SEQ ID NO:115), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa

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PCT/US2014/049254 gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccccagctccagctccaggaagcgcgcgcaacggagaccac tgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtc gctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgc aagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaac atgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggt gccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattc aaaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcc aaagactgccactgcatatga (SEQ ID NO:114).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO:115.

II.G.4 HSA-GS(PAPAP)₂GS- GDF 15

The designation “HSA-GS(PAPAP)₂GS-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 116 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSAGS(PAPAP)₂GS-GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID

ΝΟΤΙΟ;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GSPAPAPPAPAPGS (SEQ ID NO:116) each linking the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

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In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE

CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD FAAFVE KC C KADDKETCFAE E GKKLVAA S QAAL G LGSPAPAPPAPAPGSA

RNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQ FRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTY DDLLAKDCHCI (SEQ ID NO:118), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget

WO 2015/017710

PCT/US2014/049254 gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccccagctccagctccacccgcacctgcccctggaagcgcg cgcaacggagaccactgtccgctcgggcccgggcgttgctgccgtctgca cacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgt cgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccag ttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcct gaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatc ccatggtgctcattcaaaagaccgacaccggggtgtcgctccagacctat gatgacttgttagccaaagactgccactgcatatga (SEQ ID N0:117).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO:118.

II.G.5 HSA-GSAAQAAQQGS-GDF15

The designation “HSA-GSAAQAAQQGS-GDF15 in the instant disclosure refers to a fusion protein comprising a GDF 15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO:119 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSA35 GSAAQAAQQGS-GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

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More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 110;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ 5 ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GSAAQAAQQGS (SEQ ID NO:119) each linking the N-terminus of the GDF 15 polypeptide to the C-terminus of an HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker double underlined):

DAHKSEVAHRFKDIGEENFKAIVIIAFAQYIQQCPFEDHVKIVNEVTEFA

KTCVADESAENCDKSIHTIFGDKICTVATIRETYGEMADCCAKQEPERNE

CFIQHKDDNPNIPRIVRPEVDVMCTAFHDNEETFIKKYIYEIARRHPYFY

APEIIFFAKRYKAAFTECCQAADKAACIIPKIDEIRDEGKASSAKQRIKC ASIQKFGERAFKAWAVARISQRFPKAEFAEVSKIVTDITKVHTECCHGDI IECADDRADIAKYICENQDSISSKIKECCEKPIIEKSHCIAEVENDEMPA

DIPSIAADFVESKDVCKNYAEAKDVFIGMFIYEYARRHPDYSVVIIIRIA

KTYETTIEKCCAAADPHECYAKVFDEFKPIVEEPQNIIKQNCEIFEQIGE

YKFQNAIIVRYTKKVPQVSTPTIVEVSRNIGKVGSKCCKHPEAKRMPCAE DYISVVINQICVIHEKTPVSDRVTKCCTESIVNRRPCFSAIEVDETYVPK EFNAETFTFHADICTISEKERQIKKQTAIVEIVKHKPKATKEQIKAVMDD

FAAFVEKCCKADDKETCFAEEGKKIVAASOAAIGIGSAAQAAOOGSARNG

DHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQVTMCIGACPSQFRA

ANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKTDTGVSIQTYDDI IAKDCHCI (SEQ ID NO:121), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat

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PCT/US2014/049254 ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccgccgctcaggctgcacagcaaggaagcgcgcgcaacgga gaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccg cgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggg aggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcg gcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccga cacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgc tcattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttg ttagccaaagactgccactgcatatga (SEQ ID NO:120).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO: 121.

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11.G.6 HSA-GS(AAQAAQQ)₂GS-GDF15

The designation “HSA-GS(AAQAAQQ)₂GS-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF 15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 122 that connects the N-terminus of the

GDF 15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSAGS(AAQAAQQ)₂GS-GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 110;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GSAAQAAQQAAQAAQQGS (SEQ ID NO:122) each linking the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence 20 (linker double underlined):

DAHKSEVAHREKDIGEENEKAIVIIAEAQYIQQCPFEDHVKIVNEVTEFA

KTCVADESAENCDKSIHTIFGDKICTVATIRETYGEMADCCAKQEPERNE

CFIQHKDDNPNIPRIVRPEVDVMCTAFHDNEETFIKKYIYEIARRHPYFY

APEIIFFAKRYKAAFTECCQAADKAACIIPKIDEIRDEGKASSAKQRIKC

ASIQKFGERAFKAWAVARISQRFPKAEFAEVSKIVTDITKVHTECCHGDI IECADDRADIAKYICENQDSISSKIKECCEKPIIEKSHCIAEVENDEMPA

DIPSIAADFVESKDVCKNYAEAKDVFIGMFIYEYARRHPDYSVVIIIRIA

KTYETTIEKCCAAADPHECYAKVFDEFKPIVEEPQNIIKQNCEIFEQIGE

YKFQNAIIVRYTKKVPQVSTPTIVEVSRNIGKVGSKCCKHPEAKRMPCAE

DYISVVINQICVIHEKTPVSDRVTKCCTESIVNRRPCFSAIEVDETYVPK EFNAETFTFHADICTISEKERQIKKQTAIVEIVKHKPKATKEQIKAVMDD

FAAFVEKCCKADDKETCFAEEGKKIVAASOAAIGIGSAAQAAQQAAQAAQ

QfifiARNGDHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQVTMCIGA

CPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKTDTGVS

IQTYDDIIAKDCHCI (SEQ ID NO:124),

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PCT/US2014/049254 which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccgccgctcaggctgcacagcaagcagcccaagcagctcag

100

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PCT/US2014/049254 cagggaagcgcgcgcaacggagaccactgtccgctcgggcccgggcgttg ctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccg attgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcg tgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgag cctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccg ccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcg ctccagacctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:123).

As discussed above, in a specific embodiment, a homodimer is provided comprising 10 two fusion proteins having the sequence of SEQ ID NO: 124.

II.G. 7 HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15

The designation “HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to an HSA 15 polypeptide via a linker comprising the sequence of SEQ ID NO: 125 that connects the

N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSAGGNAEAAAKEAAAKEAAAKAGG-GDF15 fusion proteins, linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 110;

(b) two GDF15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

GGNAEAAAKEAAAKEAAAKAGG (SEQ ID NO:125) each linking the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence 30 (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE

CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY

APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC

ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL

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LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE

DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD

FAAFVEKCCKADDKETCFAEEGKKLVAASQAALGLGGNAEAAAKEAAAKE

AAAKEAAAKAGGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE

VQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVL

IQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:127), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca

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PCT/US2014/049254 agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggcaacgccgaggctgccgctaaggaagccgctgccaaggag gccgcagcaaaagaggctgcagctaaggccggaggagcgcgcaacggaga ccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcg cgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgggag gtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggc aaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgaca cggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctc attcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgtt agccaaagactgccactgcatatga (SEQ ID NO:126).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO: 127.

II.G.8 HSA-(G₄S)₆-GDF15

The designation “HSA-(G4S)6-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF 15 polypeptide linked to an HSA polypeptide via a linker comprising the sequence of SEQ ID NO: 128 that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSA-(G₄S)₆GDF15 fusion proteins, linked via an interchain disulfide bond between their respective

GDF15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 110;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ

ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence:

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GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:128) each linking the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence 5 (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE

CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY

APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD

FAAFVEKCCKADDKETCFAEEGKKLVAASOAALGLGGGGSGGGGSGGGGS

GGGGSGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLS

PREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNP MVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:130), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaattgtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc

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PCT/US2014/049254 tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggtggtggctctggaggcggtggaagcggaggcggtggatcc ggaggcggtggaagcggaggtggtggatctggaggcggtggaagcgcgcg caacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcaca cggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcg ccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagtt ccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctga agcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatccc atggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatga tgacttgttagccaaagactgccactgcatatga (SEQ ID NO:129).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO: 130.

II.G.9 HSA-GS(AAQAAQQ)₂GS-GDF15(N3D)

The designation “HSA-GS(AAQAAQQ)₂GS-GDF15(N3D)” in the instant disclosure refers to a fusion protein comprising a GDF15(N3D) polypeptide linked to an HSA

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PCT/US2014/049254 polypeptide via a linker comprising the sequence of SEQ ID NO: 122 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the HSA polypeptide.

In certain embodiments, a homodimer is provided comprising two HSAGS(AAQAAQQ)₂GS-GDF15(N3D) fusion proteins, linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two HSA polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 110;

(b) two GDF15(N3D) polypeptides (one each monomer) comprising the sequence of 10 SEQIDNO:52; and (c) two polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO:122 each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of an HSA polypeptide via a peptide bond.

In a preferred embodiment, the fusion protein comprises the amino acid sequence 15 (linker double underlined):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE

CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY

APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC

ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE

YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE

DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD

FAAFVEKCCKADDKETCFAEEGKKLVAASOAALGLGSAAQAAQQAAQAAQ

20ARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGA

CPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVS

LQTYDDLLAKDCHCI (SEQ ID NO:242), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgg gagaagaaaatttcaaagccttggtgttgattgcctttgctcagtatctt cagcagtgtccatttgaagatcatgtaaaattagtgaatgaagtaactga atttgcaaaaacatgtgttgctgatgagtcagctgaaaattgtgacaaat cacttcataccctttttggagacaaattatgcacagttgcaactcttcgt

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PCT/US2014/049254 gaaacctatggtgaaatggctgactgctgtgcaaaacaagaacctgagag aaatgaatgcttcttgcaacacaaagatgacaacccaaacctcccccgat tggtgagaccagaggttgatgtgatgtgcactgcttttcatgacaatgaa gagacatttttgaaaaaatacttatatgaaattgccagaagacatcctta cttttatgccccggaactccttttctttgctaaaaggtataaagctgctt ttacagaatgttgccaagctgctgataaagctgcctgcctgttgccaaag ctcgatgaacttcgggatgaagggaaggcttcgtctgccaaacagagact caagtgtgccagtctccaaaaatttggagaaagagctttcaaagcatggg cagtagctcgcctgagccagagatttcccaaagctgagtttgcagaagtt tccaagttagtgacagatcttaccaaagtccacacggaatgctgccatgg agatctgcttgaatgtgctgatgacagggcggaccttgccaagtatatct gtgaaaatcaagattcgatctccagtaaactgaaggaatgctgtgaaaaa cctctgttggaaaaatcccactgcattgccgaagtggaaaatgatgagat gcctgctgacttgccttcattagctgctgattttgttgaaagtaaggatg tttgcaaaaactatgctgaggcaaaggatgtcttcctgggcatgtttttg tatgaatatgcaagaaggcatcctgattactctgtcgtgctgctgctgag acttgccaagacatatgaaaccactctagagaagtgctgtgccgctgcag atcctcatgaatgctatgccaaagtgttcgatgaatttaaacctcttgtg gaagagcctcagaatttaatcaaacaaaattgtgagctttttgagcagct tggagagtacaaattccagaatgcgctattagttcgttacaccaagaaag taccccaagtgtcaactccaactcttgtagaggtctcaagaaacctagga aaagtgggcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctg tgcagaagactatctatccgtggtcctgaaccagttatgtgtgttgcatg agaaaacgccagtaagtgacagagtcaccaaatgctgcacagaatccttg gtgaacaggcgaccatgcttttcagctctggaagtcgatgaaacatacgt tcccaaagagtttaatgctgaaacattcaccttccatgcagatatatgca cactttctgagaaggagagacaaatcaagaaacaaactgcacttgttgag ctcgtgaaacacaagcccaaggcaacaaaagagcaactgaaagctgttat ggatgatttcgcagcttttgtagagaagtgctgcaaggctgacgataagg agacctgctttgccgaggagggtaaaaaacttgttgcggccagtcaggcc gccttaggcttaggatccgccgctcaggctgcacagcaagcagcccaagc agctcagcagggaagcgcgcgcgacggagaccactgtccgctcgggcccg ggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggc tgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcat cggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatca agacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgc gtgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccgg

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PCT/US2014/049254 ggtgtcgctccagacctatgatgacttgttagccaaagactgccactgca ta (SEQ ID NO:241).

As discussed above, in a specific embodiment, a homodimer is provided comprising two fusion proteins having the sequence of SEQ ID NO:242.

II.H, Constructs with Mutations to Address Affinity for FcyR Binding

It was found that certain charged pair (delHinge) multimers exhibited Fey receptor (FcyR) binding, particularly to FcyRI and FcyRIII. See, e.g., Example 7. In some cases, the FcyR binding affinity was comparable to that of observed in multimers comprising a hinge region. This was unexpected, because the Fey receptor interacts with the hinge region and these multimers were delHinge, as described above, lacking all or part of the hinge region. Mutational analyses of the Fc residues involved in binding to FcyR suggest that the main interaction site is localized in the hinge region and CH2 domain (Tamm A, 1997, Int. Rev. Immunol. 16:57-85). See also, Radaev S, et al., J. Biol. Chem. 276:16469-16477;

Sondermann, P, et al., 2000, Nature 406:267-273.

Antibody-dependent cellular cytotoxicity (ADCC), an immune response mediated primarily by natural killer (NK) cells in humans, depends on the interaction of FcyRs, especially FcyRIIIA in humans, with the Fc domain of an antibody or Fc-containing protein. In ADCC, Fc binding to FcyRIII on the surface of an NK cell activates the NK cell, which releases perforins and granzymes.

Accordingly, constructs are provided having additional modifications to modulate the interaction of the construct with the FcyR. In one series of embodiments, an asparagine to glycine mutation (N297G) is introduced to a native Fc or Fc variant, including the various Fc domains described above. The N297G mutation removes a conserved N-glycosylation site at in the CH2 domain.

In another series of embodiments, additional N-terminal amino acid residues are deleted from an Fc domain from which all or a portion of the hinge region has been removed. For example, the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NQ:303)

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PCT/US2014/049254 is provided by deletion of amino acid residues N-terminal to G236 of the Fe domain of wildtype IgGl. In some embodiments, the C-terminal lysine (K447) optionally may be deleted from this Fe variant. The amino acid sequence:

GPSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTI SKAKGQPREPQVYTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQ PENNYKTTPPVIDSDGSFFIYSKITVDKSRWQQGNVFSCSVMHEAIHNHY TQKSLSLSPGK (SEQ ID NO:304) is provided by deletion of amino acid residues N-terminal to G237 from the Fe domain of 10 wild-type IgGl. In some embodiments, the C-terminal lysine (K447) optionally may be deleted from this Fe variant. The amino acid sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

KAKGQPREPQVYTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYKTTPPVIDSDGSFFIYSKITVDKSRWQQGNVFSCSVMHEAIHNHYT QKSISISPGK (SEQ ID NO:305) is provided by deletion of amino acid residues N-terminal to P238 of the Fe domain of wildtype IgGl. In some embodiments, the C-terminal lysine (K447) optionally may be deleted from this Fe variant.

In one embodiment, a DhCpmFc(-) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(-)(N297G)” domain). In another embodiment, a DhCpmFc(+) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(+)(N297G)” domain).

In another embodiment, a DhCpmFc(-)(Y349C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(-)(N297G)(Y349C)” domain). In another embodiment, a DhCpmFc(+)(S354C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(+)(N297G)(S354C)” domain).

In another embodiment, a DhCpmFc(+)(Y349C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(+)(N297G)(Y349C)”domain). In another embodiment, a DhCpmFc(-)(S354C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as “DhCpmFc(-)(N297G)(S354C)” domain).

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In another embodiment, a DhCpmFc(+)(L351C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(+)(N297G)( L351C)” domain). In another embodiment, a DhCpmFc(-)(L351C) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “DhCpmFc(-)(N297G)( L351C)” domain).

In another embodiment, a DhCpmFc(-) domain into which an alanine to cysteine mutation (A287C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(A287C)” domain). In another embodiment, a DhCpmFc(+) domain into which an alanine to cysteine mutation (A287C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(A287C)” domain).

In another embodiment, a DhCpmFc(-) domain into which a leucine to cysteine mutation (L306C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(L306C)” domain). In another embodiment, a DhCpmFc(+) domain into which a leucine to cysteine mutation (L306C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(L306C)” domain).

In another embodiment, a DhCpmFc(-)(A287C) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(A287C)(Y349C)” domain). In another embodiment, a DhCpmFc(+)(A287C) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(A287C)(Y349C)” domain).

In another embodiment, a DhCpmFc(-)(A287C) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(A287C)(S354C)” domain). In another embodiment, a DhCpmFc(+)(A287C) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(A287C)(S354C)” domain).

In another embodiment, a DhCpmFc(-)(L306C) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(L306C)(Y349C)” domain). In another embodiment, a DhCpmFc(+)(L306C) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(L306C)(Y349C)” domain).

In another embodiment, a DhCpmFc(-)(L306C) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “DhCpmFc(-)(L306C)(S354C)” domain). In another embodiment, a DhCpmFc(+)(L306C) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “DhCpmFc(+)(A287C)( L306C)” domain).

In another embodiment, a DhCpmFc(-) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc(-)” domain). In

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PCT/US2014/049254 another embodiment, a DhCpmFc(+) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc(+)” domain).

In another embodiment, a DhCpmFc(-)(Y349C) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc(-)(Y349C)” domain). In another embodiment, a DhCpmFc(+)(S354C) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc(+)(S354C)” domain).

In another embodiment, a DhCpmFc(+)(Y349C) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc(+)(Y349C)” domain). In another embodiment, a DhCpmFc(-)(S354C) domain from which the N-terminal 7 amino acids have been removed is provided (referred to herein as a “Dh2CpmFc()(S354C)” domain).

In another embodiment, a CpmFc(+) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “CpmFc(+)(N297G)”domain). In another embodiment, a CpmFc(-) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “CpmFc(-)(N297G)” domain).

In another embodiment, a Dh2CpmFc(+) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “Dh2CpmFc(+)(N297G)”domain). In another embodiment, a Dh2CpmFc(-) domain into which an asparagine to glycine mutation (N297G) has been introduced is provided (referred to herein as a “Dh2CpmFc(-)(N297G)”domain).

In another embodiment, a Dh2CpmFc(-)(N297G) domain into which an alanine to cysteine mutation (A287C) has been introduced is provided (referred to herein as a “Dh2CpmFc(-)(N297G)(A287C)” domain). In another embodiment, Dh2CpmFc(+)(N297G) domain into which a leucine to cysteine mutation (L306C) has been introduced is provided (referred to herein as a “Dh2CpmFc(+)(N297G)(L306C)” domain).

In another embodiment, a Dh2CpmFc(-)(N297G)(A287C) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “Dh2CpmFc(-)(N297G)(A287C)(Y349C)” domain). In another embodiment, a

Dh2CpmFc(+)(N297G)(L306C) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “Dh2CpmFc(+)(N297G)(L306C)(S354C)” domain).

In another embodiment, a Dh2CpmFc(-) domain onto which two glycines have been added to the N-terminus is provided (referred to herein as a “GG-Dh2CpmFc(-)(N297G)” domain). In another embodiment, a Dh2CpmFc(+) domain onto which two glycines have ill

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PCT/US2014/049254 been added to the N-terminus is provided (referred to herein as a “GGDh2CpmFc(+)(N297G)” domain).

In another embodiment, a GG-Dh2CpmFc(-) domain into which a tyrosine to cysteine mutation (Y349C) have been introduced is provided (referred to herein as a “GG5 Dh2CpmFc(-)(Y349C)” domain). In another embodiment, a GG-Dh2CpmFc(+) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “GG-Dh2CpmFc(+)(S354C)” domain).

In another embodiment, a GG-Dh2CpmFc(+) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “GG10 Dh2CpmFc(+)(Y349C)” domain). In another embodiment, a GG-Dh2CpmFc(-) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “GG-Dh2CpmFc(-)(S354C)” domain).

In another embodiment, a Dh2CpmFc(-) domain onto which a glycine has been added to the N-terminus is provided (referred to herein as a “Dh3CpmFc(-)(N297G)” domain). In another embodiment, a Dh2CpmFc(+) domain onto which a glycine has been added to the Nterminus is provided (referred to herein as a “Dh3CpmFc(+)” domain).

In another embodiment, a Dh3CpmFc(-) domain into which a tyrosine to cysteine mutation (Y349C) has been introduced is provided (referred to herein as a “Dh3CpmFc(-)(Y349C)” domain). In another embodiment, a Dh3CpmFc(+) domain into which a serine to cysteine mutation (S354C) has been introduced is provided (referred to herein as a “Dh3CpmFc(+)(S354C)” domain).

In another embodiment, an asparagine to glycine mutation (N297G) is introduced into a DhMonoFc domain (referred to herein as “DhMonoFc(N297G)”).

II.H.l DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G)

The designation “DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the Cterminus of a DhCpmFc(-)(N297G) domain, and (ii) a second polypeptide chain comprising a

DhCpmFc(+)(N297G) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG(SEQ ID NO:287), (b) two DhCpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:132), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO :134), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag

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PCT/US2014/049254 tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:133).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

APEIIGGPSVFIFPPKPKDTIMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPA PIEKTISKAKGQPREPQVYTIPPSRKEMTKNQVSITCIVKGFYPSDIAVE WESNGQPENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHE AIHNHYTQKSISISPGK(SEQ ID NO:131), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctgaagtccgacggctccttcttcctctatagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa atga (SEQ ID NO:135).

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 134 and two polypeptide chains comprising the sequence of SEQ ID NO: 131.

11.H.2 DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G)

The designation “DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) sequence, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G) domain, and (ii) a second polypeptide chain comprising a

DhCpmFc(+)(N297G) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO:287, (b) two DhCpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 132, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN

PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:137), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg

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PCT/US2014/049254 gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:136).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:131, which is encoded by the nucleic acid sequence of SEQ ID NO:135.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:137 and two polypeptide chains comprising the sequence of SEQ ID NO: 131.

II.H.3 DhCpmFc(-)(N297G)-G₄-GDF15(N3D):DhCpmFc(+)(N297G)

The designation “DhCpmFc(-)(N297G)-G4-GDF15(N3D):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide linked to a DhCpmFc(-)(N297G) domain via a linker comprising the sequence of SEQ ID NO:58 that connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(N297G) domain and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(N297G)-G4-GDF15(N3D):DhCpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

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PCT/US2014/049254 (a) two DhCpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO:287, (b) two DhCpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 132, (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52, and (d) two polypeptide linkers (one each heterodimer) comprising the sequence of SEQ ID NO:58 each linking the N-terminus of a GDF15(N3D) polypeptide to the C-terminus of a DhCpmFc(-)(N297G) domain via a peptide bond.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGARDGDHCPLGPGRCCRLHTVRASLEDLGWA

DWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:139), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggagcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggcc gattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgc

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PCT/US2014/049254 gtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacga gcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgccc gccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID

NO:138) .

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:131, which is encoded by the nucleic acid sequence of SEQ ID NO:135.

As discussed above, a tetramer is provided comprising two polypeptide chains 10 comprising the sequence of SEQ ID NO:139 and two polypeptide chains comprising the sequence of SEQ ID NO: 131.

II.H.4 DhCpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C)

The designation “DhCpmFc(-)(N297G)(Y349C)15 GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(S354C) domains (one each heterodimer) comprising the sequence:

APEIIGGPSVFIFPPKPKDTIMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPA PIEKTISKAKGQPREPQVYTIPPCRKEMTKNQVSITCIVKGFYPSDIAVE WESNGQPENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHE AIHNHYTQKSISISPG (SEQ ID NO:288), (b) two DhCpmFc(-)(N297G)(Y349C) domains (one each heterodimer) comprising the sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:141), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO :143), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg

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In a preferred embodiment, the second polypeptide chain comprises the amino acid 5 sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGK (SEQ ID NO :140), which is encoded by the nucleic acid sequence:

gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacgg gagcacctaccgcgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcactgtccctgtctccgggtaa a (SEQ ID NO:144).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 143 and two polypeptide chains comprising the sequence of SEQ ID NO: 140.

11H.5 DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C)

The designation “DhCpmFc(-)(N297G)(Y349C)GDF15(N3D):DhCpmFc(+)(N297G)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a

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DhCpmFc(-)(N297G)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(S345C) domain, The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:288, (b) two DhCpmFc(-)(N297G)(Y349C) domains comprising the sequence of SEQ ID NO:141, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence 15 of SEQ IDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 20 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:146), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt

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PCT/US2014/049254 gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:145).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140, which is encoded by the nucleic acid sequence of SEQ ID NO:144.

As discussed above, a tetramer is provided comprising two polypeptide chains 15 comprising the sequence of SEQ ID NO: 146 and two polypeptide chains comprising the sequence of SEQ ID NO: 140.

11.H.6 DhCpmFc(-)(N297G)(L351C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C)

The designation “DhCpmFc(-)(N297G)(L351C)20 GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(L351C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(L351C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)(L351C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L351C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE

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WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:289), (b) two DhCpmFc(-)(N297G)(L351C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:148), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL

SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:150), which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaacagtatgg cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgagccgcaaagaaatgaccaaaaaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactataaaaccaccccgccggt gctgaaaagcgatggcagcttttttctgtatagcaaactgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcgtgatgcatgaa

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PCT/US2014/049254 gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgc gcgcaacggcgatcattgcccgctgggcccgggccgctgctgccgcctgc ataccgtgcgcgcgagcctggaagatctgggctgggcggattgggtgctg agcccgcgcgaagtgcaggtgaccatgtgcattggcgcgtgcccgagcca gtttcgcgcggcgaacatgcatgcgcagattaaaaccagcctgcatcgcc tgaaaccggataccgtgccggcgccgtgctgcgtgccggcgagctataac ccgatggtgctgattcagaaaaccgataccggcgtgagcctgcagaccta tgatgatctgctggcgaaagattgccattgcatt (SEQ ID NO:149).

In a preferred embodiment, the second polypeptide chain comprises the amino acid 10 sequence:

APEIIGGPSVFIFPPKPKDTIMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPA

PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSITCIVKGFYPSDIAVE

WESNGQPENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHE

AIHNHYTQKSISISPGK (SEQ ID NO :147), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacacctgtcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa a (SEQ ID NO:151).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:150 and two polypeptide chains comprising the sequence of SEQ ID NO: 147.

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11.H.7 DhCpmFc(-)(N297G)(L351C)-GDF15(N3D):DhCpmFc(+)(N297G)(L351C)

The designation “DhCpmFc(-)(N297G)(L351C)GDF15(N3D):DhCpmFc(+)(N297G)(L351C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(L351C) domain by a peptide bond and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(L351C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(N297G)(L351C)-GDF15(N3D):DhCpmFc(+)(N297G)(L351C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L351C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:289, (b) two DhCpmFc(-)(N297G)(L351C) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 148, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:153), which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaacagtatgg cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc

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PCT/US2014/049254 tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgagccgcaaagaaatgaccaaaaaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactataaaaccaccccgccggt gctgaaaagcgatggcagcttttttctgtatagcaaactgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcgtgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgc gcgcgatggcgatcattgcccgctgggcccgggccgctgctgccgcctgc ataccgtgcgcgcgagcctggaagatctgggctgggcggattgggtgctg agcccgcgcgaagtgcaggtgaccatgtgcattggcgcgtgcccgagcca gtttcgcgcggcgaacatgcatgcgcagattaaaaccagcctgcatcgcc tgaaaccggataccgtgccggcgccgtgctgcgtgccggcgagctataac ccgatggtgctgattcagaaaaccgataccggcgtgagcctgcagaccta tgatgatctgctggcgaaagattgccattgcatt (SEQ ID NO:152).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147, which is encoded by the nucleic acid sequence of SEQ ID

NO:151.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:153 and two polypeptide chains comprising the sequence of SEQ ID NO: 147.

11.H.8 DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)

The designation “DhCpmFc(-)(N297G)(A287C)25 GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(A287C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(L306C) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C) domains (one each heterodimer) comprising the sequence:

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APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:290), (b) two DhCpmFc(-)(N297G)(A287C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:268), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:269), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc

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PCT/US2014/049254 cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:270).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:267), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtacaccctgcccccatcccggaaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgc ctcccgtgctgaagtccgacggctccttcttcctctatagcaagctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtaaa (SEQ ID NO:271) .

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:269 and two polypeptide chains comprising the sequence of SEQ ID NO:267.

II.H.9 DhCpmFc(-)(N297G)(A287C)-GDF15(N3D):DhCpmFc(+)(N297G)(L306C)

The designation “DhCpmFc(-)(N297G)(A287C)GDF15(N3D):DhCpmFc(+)(N297G)(L306C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a

DhCpmFc(-)(N297G)(A287C) domain, and (ii) a second polypeptide chain comprising a

DhCpmFc(+)(N297G)(L306C) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)(A287C)-GDF15(N3D):DhCpmFc(+)(N297G)(L306C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:290, (b) two DhCpmFc(-)(N297G)(A287C) domains (one each heterodimer) comprising 20 the sequence of SEQ ID NO:268, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid 25 sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:272), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:267, which is encoded by the nucleic acid sequence of SEQ ID

NO:271.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:272 and two polypeptide chains comprising the sequence of SEQ ID NO:267.

11.H.10 DhCpmFc(-)(N297G)(A287C)(Y349C)-GDF 15(Ndel3):

DhCpmFc(+)(N297G)(L306C)(S354C)

The designation “DhCpmFc(-)(N297G)(A287C)(Y349C)30 GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(L306C)(S354C) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

DhCpmFc(-)(N297G)(A287C)(Y349C)GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)(S354C) heterodimers in which the two first

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More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C)(Y349C) domains (one each heterodimer) 5 comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:291), (b) two DhCpmFc(-)(N297G)(A287C)(S354C) domains (one each heterodimer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA 15 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:275), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA 25 PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:276), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta

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PCT/US2014/049254 cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtgcaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:277).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:274), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtgctccaccag gactggcttaatgggaaggaatacaagtgtaaggtgtccaacaaggccct ccccgctcccatcgaaaagaccatctcaaaggcaaaggggcaaccaaggg aacctcaagtgtacaccctgcctccgtgcaggaaggagatgaccaagaac caggtcagcctgacttgtctcgtgaagggcttctatcccagcgatattgc tgtggaatgggagtcaaatggccagcccgagaataactacaaaactaccc

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PCT/US2014/049254 cacccgtgctgaaatctgatgggtccttcttcctttactccaagctgacc gtggacaagagccgctggcaacaaggcaatgtctttagctgctcagtgat gcatgaggctctccataatcactacactcagaagtcactgtccctgtctc cgggtaaa (SEQ ID NO:278).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:276 and two polypeptide chains comprising the sequence of SEQ ID NO:274.

II.H. 11 DhCpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D):

DhCpmFc(+)(N297G)(L306C)(S354C)

The designation “DhCpmFc(-)(N297G)(A287C)(Y349C)GDF15(N3D):DhCpmFc(+)(N297G)(L306C)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhCpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+)(N297G)(L306C)(S354C) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two DhCpmFc(-)(N297G)(A287C)(Y349C)20 GDF15(N3D):DhCpmFc(+)(N297G)(L306C)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:291, (b) two DhCpmFc(-)(N297G)(A287C)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:275, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL

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SPREVQVTMCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYN PMVIIQKTDTGVSIQTYDDIIAKDCHCI (SEQ ID NO:279), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc 5 caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtgcaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtgcgcgcgacggagaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:280).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:274, which is encoded by the nucleic acid sequence of SEQ ID NO:278.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:279 and two polypeptide chains comprising the sequence of SEQ ID NO:274.

II.H. 12 Dh2CpmFc(-)-GDF 15(Ndel3) :Dh2CpmFc(+)

The designation “Dh2CpmFc(-)-GDF15(Ndel3):Dh2CpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a

Dh2CpmFc(-) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+) domain.

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In certain embodiments, a tetramer is provided, comprising a dimer of two Dh2CpmFc(-)-GDF15(Ndel3):Dh2CpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG(SEQ ID NO:292), (b) two Dh2CpmFc(-) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 15 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG(SEQ ID NO:155), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 25 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:157), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc

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PCT/US2014/049254 aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:156).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK(SEQ ID NO:154), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccggaaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacaagaccacgcctcccgtgctgaagtccgacggctcctt

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PCT/US2014/049254 cttcctctatagcaagctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtaaatga (SEQ ID NO:158)

As discussed above, a tetramer is provided comprising two polypeptide chains 5 comprising the sequence of SEQ ID NO:157 and two polypeptide chains comprising the sequence of SEQ ID NO: 154.

ll.H. 13 Dh2CpmFc(-)-GDF15(N3D):Dh2CpmFc(+)

The designation “Dh2CpmFc(-)-GDF15(N3D):Dh2CpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a Dh2CpmFc(-) domain by a peptide bond, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)-GDF15(N3D):DhCpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+) domains (one each heterodimer) comprising the sequence of

SEQ ID NO:292, (b) two Dh2CpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 155, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:160), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:159).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154, which is encoded by the nucleic acid sequence of SEQ ID NO:158.

As discussed above, a tetramer is provided comprising two polypeptide chains 25 comprising the sequence of SEQ ID NO: 160 and two polypeptide chains comprising the sequence of SEQ ID NO: 154.

ll.H. 14 Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(S354C)

The designation “Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(S354C)” in 30 the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the Cterminus of a Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

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In certain embodiments, a tetramer is provided, comprising a dimer of two Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 10 KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:293), (b) two Dh2CpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:162), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC

IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:164), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:163).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:161), which is encoded by the nucleic acid sequence:

ccatccgtgttcctgtttcctccaaagccgaaggacaccctgatgatctc aagaactccggaagtgacttgcgtcgtcgtggacgtgtcacatgaggatc cagaggtcaagttcaattggtatgtggacggagtggaagtgcataacgcc aagaccaaaccccgcgaagaacagtacaatagcacctaccgcgtggtgag cgtccttactgtgctccaccaggactggcttaatgggaaggaatacaagt gtaaggtgtccaacaaggccctccccgctcccatcgaaaagaccatctca aaggcaaaggggcaaccaagggaacctcaagtgtacaccctgcctccgtg

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PCT/US2014/049254 caggaaggagatgaccaagaaccaggtcagcctgacttgtctcgtgaagg gcttctatcccagcgatattgctgtggaatgggagtcaaatggccagccc gagaataactacaaaactaccccacccgtgctgaaatctgatgggtcctt cttcctttactccaagctgaccgtggacaagagccgctggcaacaaggca atgtctttagctgctcagtgatgcatgaggctctccataatcactacact cagaagtcactgtccctgtctccgggtaaa (SEQ ID NO:165).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 164 and two polypeptide chains comprising the sequence of SEQ ID NO: 161.

11.H.15 Dh2CpmFc(-)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(S354C)

The designation “Dh2CpmFc(-)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C15 terminus of a Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(S354C) heterodimers in which two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:293, (b) two Dh2CpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 162, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

KAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNHYT QKSISISPGARDGDHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQV

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TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:167), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc 5 ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:166).

In a preferred embodiment, the second monomer comprises the amino acid sequence of SEQ ID NO:161, which is encoded by the nucleic acid sequence of SEQ ID NO:165.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 167 and two polypeptide chains comprising the sequence of SEQ ID NO: 161.

II.H.16 CpmFc(-)(N297G)-GDF15(Ndel3):CpmFc(+)(N297G)

The designation “CpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain comprising a

CpmFc(+)(N297G) domain.

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In certain embodiments, a tetramer is provided, comprising a dimer of two CpmFc(-)(N297G)-GDF15(Ndel3):CpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two CpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence (part of the hinge region in parentheses):

(DKTHTCPPCP)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKE

YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO :294), (b) two CpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence (part of the hinge region in parentheses):

(DKTHTCPPCP)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:169), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

(DKTHTCPPCP)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLE

DLGWADWVL S PREVQVTMCIGAC PSQFRAANMHAQIKT S LHRLKPDTVPA

PCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:171), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 gacaaaactcacacatgcccaccgtgcccagcacctgaactcc tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgc ataatgccaagacaaagccgcgggaggagcagtacggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatg ggcagccggagaacaactacgacaccacgcctcccgtgctggactccgac ggctccttcttcctctatagcgacctcaccgtggacaagagcaggtggca gcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacc actacacgcagaagagcctctccctgtctccgggtggagaccactgtccg ctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgga agacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtga ccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcac gcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagc gccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaaga ccgacaccggggtgtcgctccagacctatgatgacttgttagccaaagac tgccactgcata (SEQ ID NO:170).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

(DKTHTCPPCP)APEIIGGPSVFIFPPKPKDTIMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKE YKCKVSNKAIPAPIEKTISKAKGQPREPQVYTIPPSRKEMTKNQVSITCI VKGFYPSDIAVEWESNGQPENNYKTTPPVIKSDGSFFIYSKITVDKSRWQ QGNVFSCSVMHEAIHNHYTQKSISISPGK (SEQ ID NO:168), which is encoded by the nucleic acid sequence:

gacaaaactcacacatgcccaccgtgcccagcacctgaactcc tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgc ataatgccaagacaaagccgcgggaggagcagtacggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga

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PCT/US2014/049254 gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatcccggaaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatg ggcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgac ggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggca gcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacc actacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:172).

As discussed above, a tetramer is provided comprising two polypeptide chains 10 comprising the sequence of SEQ ID NO: 171 and two polypeptide chains comprising the sequence of SEQ ID NO: 168.

II.H.17 CpmFc(-)(N297G)-GDF15(N3D):CpmFc(+)(N297G)

The designation “CpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain comprising a CpmFc(+)(N297G) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

CpmFc(-)(N297G)-GDF15(N3D):CpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two CpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence of SEQ IDNO:294, (b) two CpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 169, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

(DKTHTCPPCP)APEIIGGPSVFIFPPKPKDTIMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKE YKCKVSNKAIPAPIEKTISKAKGQPREPQVYTIPPSREEMTKNQVSITCI

VKGFYPSDIAVEWESNGQPENNYDTTPPVIDSDGSFFIYSDITVDKSRWQ QGNVFSCSVMHEAIHNHYTQKSISISPGARDGDHCPIGPGRCCRIHTVRA

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SLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDT

VPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ IDNO:174), which is encoded by the nucleic acid sequence:

gacaaaactcacacatgcccaccgtgcccagcacctgaactcc 5 tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgc ataatgccaagacaaagccgcgggaggagcagtacggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatg ggcagccggagaacaactacgacaccacgcctcccgtgctggactccgac ggctccttcttcctctatagcgacctcaccgtggacaagagcaggtggca gcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacc actacacgcagaagagcctctccctgtctccgggtgcgcgcgacggagac cactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgc gtcgctggaagacctgggctgggccgattgggtgctgtcgccacgggagg tgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggca aacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacac ggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctca ttcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgtta gccaaagactgccactgcata (SEQ ID NO:173).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168, which is encoded by the nucleic acid sequence comprising the sequence of SEQ ID NO: 172.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 174 and two polypeptide chains comprising the sequence of SEQ ID NO: 168.

11.H.18 Dh2CpmFc(-)(N297G)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)

The designation “Dh2CpmFc(-)(N297G)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C146

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In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)-GDF15(Ndel3):Dh2CpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTIS KAKGQPREPQVYTIPPSRKEMTKNQVSITCIVKGFYPSDIAVEWESNGQP ENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHEAIHNHYT QKSISISPG(SEQ ID NO:295), (b) two Dh2CpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

KAKGQPREPQVYTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNHYT QKSISISPG(SEQ ID NO:176), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTIS KAKGQPREPQVYTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNHYT QKSISISPGGDHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQVTMC IGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKTDT GVSIQTYDDIIAKDCHCI (SEQ ID NO:178), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:177).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK(SEQ ID NO:175), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc

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PCT/US2014/049254 ccggaaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacaagaccacgcctcccgtgctgaagtccgacggctcctt cttcctctatagcaagctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtaaatga (SEQ ID NO:179).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:178 and two polypeptide chains comprising the sequence of SEQ ID NO: 175.

II.H. 19 Dh2CpmFc(-)(N297G)-GDF15(N3D):Dh2CpmFc(+)(N297G)

The designation “Dh2CpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C15 terminus of a Dh2CpmFc(-)(N297G) domain, and (ti) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two Dh2CpmFc(-)(N297G)-GDF15(N3D):Dh2CpmFc(+)(N297G) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO:295, (b) two Dh2CpmFc(-)(N297G) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 176, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV

TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:181),

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ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:180).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175, which is encoded by the nucleic acid sequence of SEQ ID NO:179.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:181 and two polypeptide chains comprising the sequence of SEQ ID NO: 175.

11.H.20 Dh2CpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(S354C)

The designation “Dh2CpmFc(-)(N297G)(Y349C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a Dh2CpmFc(-)(N297G)(Y349C) polypeptide, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G)(S345C) domain. The cysteine clamp mutations allow the first and

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In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)(Y349C)-GDF 15 (Ndel3) :Dh2CpmFc(+)(N297G)(S3 54C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G)(S354C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:296), (b) two Dh2CpmFc(-)(N297G)(Y349C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:183), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO :185), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacggcagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:184).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:182), which is encoded by the nucleic acid sequence:

ccatccgtgttcctgtttcctccaaagccgaaggacaccctgatgatctc aagaactccggaagtgacttgcgtcgtcgtggacgtgtcacatgaggatc cagaggtcaagttcaattggtatgtggacggagtggaagtgcataacgcc aagaccaaaccccgcgaagaacagtacgggagcacctaccgcgtggtgag cgtccttactgtgctccaccaggactggcttaatgggaaggaatacaagt gtaaggtgtccaacaaggccctccccgctcccatcgaaaagaccatctca aaggcaaaggggcaaccaagggaacctcaagtgtacaccctgcctccgtg

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PCT/US2014/049254 caggaaggagatgaccaagaaccaggtcagcctgacttgtctcgtgaagg gcttctatcccagcgatattgctgtggaatgggagtcaaatggccagccc gagaataactacaaaactaccccacccgtgctgaaatctgatgggtcctt cttcctttactccaagctgaccgtggacaagagccgctggcaacaaggca atgtctttagctgctcagtgatgcatgaggctctccataatcactacact cagaagtcactgtccctgtctccgggtaaa (SEQ ID NO:186).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 185 and two polypeptide chains comprising the sequence of SEQ ID NO: 182.

11.H.21 Dh2CpmFc(-)(N297G)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C)

The designation “Dh2CpmFc(-)(N297G)(Y349C)GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a Dh2CpmFc(-)(N297G)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G)(S345C) domain The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:296, (b) two Dh2CpmFc(-)(N297G)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 183, and (c) two GDF15(N3D) polypeptide (one each heterodimer) comprising the sequence of

SEQIDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

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QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:188), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:187).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182, which is encoded by the nucleic acid sequence of SEQ ID NO:186.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 188 and two polypeptide chains comprising the sequence of SEQ ID NO: 182.

II.H.22 Dh2CpmFc(-)(N297G)(A287C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)

The designation “Dh2CpmFc(-)(N297G)(A287C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising GDF15(Ndel3) polypeptide,

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PCT/US2014/049254 the N-terminus of which is linked directly to the C-terminus of a Dh2CpmFc(-)(N297G)(A287C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G)(L306C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C287 of the first monomer and C306 of the second monomer.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)(A2 87C)-GDF 15 (Ndel3) :Dh2CpmFc(+)(N297G)(L3 06C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, a tetramer is provided which comprises:

(a) two Dh2CpmFc(+)(N297G)(L306C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 15 KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:297), (b) two Dh2CpmFc(-)(N297G)(A287C) (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:192), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC

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IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:194), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca 5 tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtggagaccactgtccgc tcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaa gacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtgac catgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcacg cgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagcg ccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaagac cgacaccggggtgtcgctccagacctatgatgacttgttagccaaagact gccactgcata(SEQ ID NO:193).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGK (SEQ ID NO:191), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca

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PCT/US2014/049254 taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccggaaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgacg gctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:195).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 194 and two polypeptide chains comprising the sequence of SEQ ID NO: 191.

II.H.23 Dh2CpmFc(-)(N297G)(A287C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)

The designation “Dh2CpmFc(-)(N297G)(A287C)GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a

Dh2CpmFc(-)(N297G)(A287C) domain, and (ii) a second polypeptide chain comprising a

Dh2CpmFc(+)(N297G)(L306C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)(A287C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, a tetramer is provided which comprises:

(a) two Dh2CpmFc(+)(N297G)(L306C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:297, (b) two Dh2CpmFc(-)(N297G)(A287C) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 192, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

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PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

KAKGQPREPQVYTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNHYT

QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQK TDTGVSIQTYDDIIAKDCHCI (SEQ ID NO:197), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca 10 tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtgcgcgcgacggagacc actgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcg tcgctggaagacctgggctgggccgattgggtgctgtcgccacgggaggt gcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaa acatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacg gtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcat tcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgttag ccaaagactgccactgcata (SEQ ID NO:196).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 191, which is encoded by the nucleic acid sequence of SEQ ID NO:195.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO: 197 and two polypeptide chains comprising the sequence of SEQ ID NO: 191.

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PCT/US2014/049254 ll.H.24 Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3): Dh2CpmFc(+)(N297G)(L306C)(S354C)

The designation “Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)(S

354C)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a Dh2CpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G)(L306C)(S354C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain and between the C349 of the first polypeptide chain and C349 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)(S3

54C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF15 regions.

More particularly, in a specific embodiment, a tetramer is provided which comprises:

(a) two Dh2CpmFc(+)(N297G)(L306C)(S354C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:298), (b) two Dh2CpmFc(-)(N297G)(A287C)(Y349C) domains (one each heterodimer) comprising the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:199), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVIHQDWINGKEYKCKVSNKAIPAPIEKTIS 5 KAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKTDT GVSIQTYDDIIAKDCHCI (SEQ ID NO:201), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtgcaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtggagaccactgtccgc tcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaa gacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtgac catgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcacg cgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagcg ccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaagac cgacaccggggtgtcgctccagacctatgatgacttgttagccaaagact gccactgcata (SEQ ID NO:200).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

PSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

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KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:198), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatgccggaaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgacg gctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:202).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:201 and two polypeptide chains comprising the sequence of SEQ ID NO: 198.

II.H.25 Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D): Dh2CpmFc(+)(N297G)(L306C)(S354C)

The designation “Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)(S3

54C)” in the instant disclosure refers to a heterodimer comprising (i) a first monomer comprising GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the Cterminus of a Dh2CpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh2CpmFc(+)(N297G)(L306C)(S354C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain and between the C349 of the first polypeptide chain and C349 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)(S35

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4C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, a tetramer is provided which comprises:

(a) two Dh2CpmFc(+)(N297G)(L306C)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:298, (b) two Dh2CpmFc(-)(N297G)(A287C)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO: 199, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of (SEQ ID NO:52).

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRVVSVCTVIHQDWINGKEYKCKVSNKAIPAPIEKTIS

KAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQK TDTGVSIQTYDDIIAKDCHCI (SEQ ID NO:204), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtgcaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtgcgcgcgacggagacc actgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcg tcgctggaagacctgggctgggccgattgggtgctgtcgccacgggaggt gcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaa

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 198, which is encoded by the nucleic acid sequence of SEQ ID NO:202.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:204 and two polypeptide chains comprising the sequence of SEQ ID NO: 198.

II.H.26 GG-Dh2CpmFc(-)-GDF15(Ndel3):GG-Dh2CpmFc(+)

The designation “GG- Dh2CpmFc(-)-GDF15(Ndel3):GG-Dh2CpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a 15 GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a

GG-Dh2CpmFc(-) domain, and (ii) a second polypeptide chain comprising a GGDh2CpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two GGDh2CpmFc(-)-GDF15(Ndel3):GG-Dh2CpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two GG-Dh2CpmFc(+) domains (one each heterodimer) comprising the sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG (SEQ ID NO:299), (b) two GG-Dh2CpmFc(-) domains (one each heterodimer) comprising the sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG (SEQ ID NO:206), and

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH

YTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVT

MCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKT DTGVSLQTYDDLLAKDCHCI (SEQ ID NO:208), which is encoded by the nucleic acid sequence:

ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcata (SEQ ID NO:207).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

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MEWSWVFLFFLSVTTGVHSGG P SVFL FPPKPKDTLMIS RT PEVT CVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRAS LEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:243), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt 10 ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcata (SEQ ID NO:244).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT

ISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG

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QPENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHEAIHNH YTQKSLSLSPGK (SEQ ID NO:205), which is encoded by the nucleic acid sequence:

ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca 5 ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttcctctatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:209).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MEWSWVFIFFISVTTGVHSGGPSVFIFPPKPKDTIMISRTPEVTCVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVITVIHQDWING KEYKCKVSNKAIPAPIEKTISKAKGQPREPQVYTIPPSRKEMTKNQVSIT CIVKGFYPSDIAVEWESNGQPENNYKTTPPVIKSDGSFFIYSKITVDKSR WQQGNVFSCSVMHEAIHNHYTQKSISISPGK (SEQ ID NO:245), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccggaaggagatgaccaagaaccaggtcagcctgacc

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PCT/US2014/049254 tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttcctctatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:246).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:208 and two polypeptide chains comprising the sequence of SEQ ID NO:205.

II.H.27 GG-Dh2CpmFc(-)-GDF15(N3D):GG-Dh2CpmFc(+)

The designation “GG-Dh2CpmFc(-)-GDF15(N3D):GG-DhCpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a GG-Dh2CpmFc(-) domain, and (ii) a second polypeptide chain comprising a GG15 DhCpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two GGDh2CpmFc(-)-GDF15(N3D):GG-Dh2CpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two GG-Dh2CpmFc(+) domains (one each heterodimer) comprising the sequence of SEQ ID NO:299, (b) two GG-Dh2CpmFc(-) domains (one each heterodimer) comprising the sequence of SEQ ID NO:206, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLI

QKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:211),

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ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgact tgttagccaaagactgccactgcata (SEQ ID NO:210).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MEWSWVFLFFLSVTTGVHSGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTV

RASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKP

DTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:247), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca

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In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:205, which is encoded by the nucleic acid sequence of SEQ ID NO:209.

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:245, which is encoded by the nucleic acid sequence of SEQ ID NO:246.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:211 and two polypeptide chains comprising the sequence of SEQ ID NO:205.

II.H.28 GG-Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):

GG-Dh2CpmFc(+)(S354C)

The designation “GG-Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):GGDh2CpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer, which comprises (i) a first polypeptide chain comprising GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus of a GG-Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a GG-Dh2CpmFc(+)(S345C) domain. The cysteine clamp

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In certain embodiments, a tetramer is provided, comprising a dimer of two GG5 Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):GG-Dh2CpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two GG-Dh2CpmFc(+)(S354C) (one each heterodimer) comprising the sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKT ISKAKGQPREPQVYTIPPCRKEMTKNQVSITCIVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSISISPG (SEQ ID NO:300), (b) two GG-Dh2CpmFc(-)(Y349C) chains (one each heterodimer) comprising the sequence:

GGPSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKT

ISKAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNG

QPENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNH YTQKSISISPG (SEQ ID NO:213), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GGPSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPAPIEKT

ISKAKGQPREPQVCTIPPSREEMTKNQVSITCIVKGFYPSDIAVEWESNG

QPENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHEAIHNH YTQKSISISPGGDHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQVT MCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKT DTGVSIQTYDDIIAKDCHCI (SEQ ID NO:215), which is encoded by the nucleic acid sequence:

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PCT/US2014/049254 ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcata (SEQ ID NO:214).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MEWSWVFLFFLSVTTGVHSGG P SVFL FPPKPKDTLMIS RT PEVT CVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRAS LEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTV

PAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI(SEQ ID NO:249), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga

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PCT/US2014/049254 ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcata (SEQ ID NO:250).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO:212), which is encoded by the nucleic acid sequence:

ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatgccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt

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PCT/US2014/049254 ccgacggctccttcttcctctatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:216).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, 5 the second polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MEWSWVFLFFLSVTTGVHSGG P SVFL FPPKPKDTLMIS RT PEVT CVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:251), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatgccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttcctctatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:252).

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:215 and two polypeptide chains comprising the sequence of SEQ ID NO:212.

II.H.29 GG-Dh2CpmFc(-)(Y349C)-GDF15(N3D):GG-Dh2CpmFc(+)(S354C)

The designation “GG-Dh2CpmFc(-)(Y349C)-GDF15(N3D):GGDh2CpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer, which comprises (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is

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PCT/US2014/049254 linked directly to the C-terminus of a GG-Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a GG-Dh2CpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two GGDh2CpmFc(-)(Y349C)-GDF15(N3D):GG-Dh2CpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two GG-Dh2CpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:300, (b) two GG-Dh2CpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:213, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLI

QKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:218), which is encoded by the nucleic acid sequence:

ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag

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PCT/US2014/049254 caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgact tgttagccaaagactgccactgcata (SEQ ID NO:217).

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MEWSWVFLFFLSVTTGVHSGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV

SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSR

WQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTV

RASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKP

DTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI(SEQ ID NO:253), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca

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PCT/US2014/049254 caaccactacacgcagaagagcctctccctgtctccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgact tgttagccaaagactgccactgcata (SEQ ID NO:254).

In a preferred embodiment, the second polypeptide chain comprises the amino acid 10 sequence of SEQ ID NO:212, which is encoded by the nucleic acid sequence of SEQ ID

NO:218.

In an embodiment employing the VH21 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:251, which is encoded by the nucleic acid sequence of SEQ ID NO:252.

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:218 and two polypeptide chains comprising the sequence of SEQ ID NO:212.

II.H.30 Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+)

The designation “Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+)” in the instant disclosure refers to a heterodimer, which comprises (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the C-terminus vof a Dh3CpmFc(-) domain, and (ii) a second polypeptide chain comprising a Dh3CpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh3CpmFc(+) domains (one each heterodimer) comprising the sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPG (SEQ ID NQ:301),

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PCT/US2014/049254 (b) two Dh3CpmFc(-) domains (one each heterodimer) comprising the sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO:220), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTM CIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI (SEQ ID NO:222), which is encoded by the nucleic acid sequence:

ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga

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PCT/US2014/049254 ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:221).

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MDMRVPAQLLGLLLLWLRGARCG PSVFL FP PKPKDT LMISRTPE VT C WV 10 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS

LTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVR

ASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPD

TVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:255), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct

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PCT/US2014/049254 cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:256).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

GPSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTI SKAKGQPREPQVYTIPPSRKEMTKNQVSITCIVKGFYPSDIAVEWESNGQ PENNYKTTPPVIKSDGSFFIYSKITVDKSRWQQGNVFSCSVMHEAIHNHY TQKSISISPGK (SEQ ID NO:219), which is encoded by the nucleic acid sequence:

ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttcctctatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:223) .

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MDMRVPAQIIGIIIIWIRGARCGPSVFIFP PKPKDTIMISRTPEVT CWV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVITVIHQDWI

NGKEYKCKVSNKAIPAPIEKTISKAKGQPREPQVYTIPPSRKEMTKNQVS ITCIVKGFYPSDIAVEWESNGQPENNYKTTPPVIKSDGSFFIYSKITVDK SRWQQGNVFSCSVMHEAIHNHYTQKSISISPGK (SEQ ID NO:257), which is encoded by the nucleic acid sequence (signal sequence underlined):

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PCT/US2014/049254 atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttcctctatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID

NO:258) .

As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:222 and two polypeptide chains comprising the sequence of SEQ IDNO:219.

II.H.31 Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+)

The designation “Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+)” in the instant disclosure refers to a heterodimer comprising (i) a first polypeptide chain comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the C-terminus of a Dh3CpmFc(-) domain, and (ii) a second polypeptide chain comprising a Dh3CpmFc(+) domain.

In certain embodiments, a tetramer is provided, comprising a dimer of two Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh3CpmFc(+) domains (one each heterodimer) comprising the sequence of SEQ ID NO:301, (b) two Dh3CpmFc(-) (one each heterodimer) comprising the sequence of SEQ ID NO:220, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:52.

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI 5 SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQ KTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:225), which is encoded by the nucleic acid sequence:

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:224).

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

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MDMRVPAQLLGLLLLWLRGARCG PSVFL FP PKPKDTIMISRTPE VT C WV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVITVIHQDWI NGKEYKCKVSNKAIPAPIEKTISKAKGQPREPQVYTIPPSREEMTKNQVS ITCIVKGFYPSDIAVEWESNGQPENNYDTTPPVIDSDGSFFIYSDITVDK

SRWQQGNVFSCSVMHEAIHNHYTQKSISISPGARDGDHCPIGPGRCCRIH TVRASIEDIGWADWVISPREVQVTMCIGACPSQFRAANMHAQIKTSIHRI KPDTVPAPCCVPASYNPMVIIQKTDTGVSIQTYDDIIAKDCHCI(SEQ ID NO:259), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct 10 gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:260).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:219, which is encoded by the nucleic acid sequence of SEQ ID NO:223.

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:257, which is encoded by the nucleic acid sequence of SEQ ID NO:258.

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:225 and two polypeptide chains comprising the sequence of SEQ IDNO:219.

II.H.32 Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(S354C)

The designation “Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer, which comprises (i) a first polypeptide chain comprising a GDF15(Ndel3) polypeptide, the N-terminus of which is linked directly to the Cterminus of a Dh3CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh3CpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

In certain embodiments, a tetramer is provided, comprising a dimer of two Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh3CpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO:302), (b) two Dh3CpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO:227), and (c) two GDF15(Ndel3) polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO:55.

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In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI 5 SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTM CIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI (SEQ ID NO:229), which is encoded by the nucleic acid sequence:

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:228).

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

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MDMRVPAQLLGLLLLWLRGARCG PSVFL FP PKPKDTIMISRTPE VT C WV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVITVIHQDWI NGKEYKCKVSNKAIPAPIEKTISKAKGQPREPQVCTIPPSREEMTKNQVS ITCIVKGFYPSDIAVEWESNGQPENNYDTTPPVIDSDGSFFIYSDITVDK

SRWQQGNVFSCSVMHEAIHNHYTQKSISISPGGDHCPIGPGRCCRIHTVR ASIEDIGWADWVISPREVQVTMCIGACPSQFRAANMHAQIKTSIHRIKPD TVPAPCCVPASYNPMVIIQKTDTGVSIQTYDDIIAKDCHCI (SEQ ID NO:261), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct 10 gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:262).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence:

GPSVFIFPPKPKDTIMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVITVIHQDWINGKEYKCKVSNKAIPAPIEKTI

SKAKGQPREPQVYTIPPCRKEMTKNQVSITCIVKGFYPSDIAVEWESNGQ

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PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK (SEQ ID NO:226), which is encoded by the nucleic acid sequence:

ggcccgtcagtcttcctcttccccccaaaaccca 5 aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatgccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttcctctatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO: 230).

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MDMRVPAQLLGLLLLWLRGARCG PSVFL FP PKPKDT LMISRTPE VT C WV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:263), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg

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As discussed above, a tetramer is provided comprising two polypeptide chains comprising the sequence of SEQ ID NO:229 and two polypeptide chains comprising the sequence of SEQ ID NO:226.

II.H.33 Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C)

The designation “Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C)” in the instant disclosure refers to a heterodimer, which comprises (i) a first polypeptide chain 15 comprising a GDF15(N3D) polypeptide, the N-terminus of which is linked directly to the Cterminus of a Dh3CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain comprising a Dh3CpmFc(+)(S345C) domain. The cysteine clamp mutations allow the first and second polypeptide chains to be linked via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

In certain embodiments, a tetramer is provided, comprising a dimer of two

Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C) heterodimers in which the two first polypeptide chains of each heterodimer are linked via an interchain disulfide bond between their respective GDF 15 regions.

More particularly, in a specific embodiment, the tetramer comprises:

(a) two Dh3CpmFc(+)(S354C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:302, (b) two Dh3CpmFc(-)(Y349C) domains (one each heterodimer) comprising the sequence of SEQ ID NO:227, and (c) two GDF15(N3D) polypeptides (one each heterodimer) comprising the sequence of SEQ IDNO:52.

In a preferred embodiment, the first polypeptide chain comprises the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI 35 SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY

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TQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQ KTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 232), which is encoded by the nucleic acid sequence:

ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:231).

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the first polypeptide chain comprises the amino acid sequence (signal sequence single underlined):

MDMRVPAQLLGLLLLWLRGARCG PSVFL FP PKPKDT LMISRTPE VT C WV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL

NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLH TVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRL KPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:265),

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atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:266).

In a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:226, which is encoded by the nucleic acid sequence of SEQ ID

NO:230.

In an embodiment employing the VK1 signal sequence, in a preferred embodiment, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:263, which is encoded by the nucleic acid sequence of SEQ ID NO:264.

As discussed above, a tetramer is provided comprising two polypeptide chains 30 comprising the sequence of SEQ ID NO:232 and two polypeptide chains comprising the sequence of SEQ ID NO:226.

II.H.34 DhMonoFc(N297G)-GDF15

The designation “DhMonoFc(N297G)-GDF15” in the instant disclosure refers to a 35 fusion protein comprising a GDF15 polypeptide, the N-terminus of which is linked directly to the C-terminus of a DhMonoFc(N297G) domain by a peptide bond.

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In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via interchain disulfide bond between their respective GDF 15 polypeptides.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (one each monomer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:233);

and (b) two GDF 15 polypeptides (one each heterodimer) comprising the sequence of SEQ ID NO: 12.

In a preferred embodiment, the fusion protein comprises the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN

PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:235), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc

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PCT/US2014/049254 cgggtgcgcgcaacggagaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:234).

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:235.

II.H. 35 DhMonoFc(N29 7G)-(G₄S)₄-GDF15

The designation “DhMonoFc(N297G)-(G4S)4-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc(N297G) domain via a linker comprising the sequence of SEQ ID NO: 18 that connects the N-terminus of the

GDF15 polypeptide to the C-terminus of the DhMonoFc(N297G) domain by a peptide bond.

In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via interchain disulfide bond between their respective GDF 15 polypeptides. More particularly, in a specific embodiment, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (one each monomer) comprising the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:236);

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ

ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO: 18 each linking the N-terminus of a GDF 15 polypeptide to the C-terminus of a DhMonoFc(N297G) domain via peptide bonds.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker double underlined):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

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ALHNHYTQKS L S L S PGGGGGSGGGGSGGGGSGGGGSARNGDHCPLGPGRC

CRLHTVRAS LEDLGWADWVL S PREVQVTMCIGAC PSQFRAANMHAQIKT S

LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID

NO:238), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggaggtggtggatccggaggcggtggaagcggaggtggtggatct ggaggcggtggaagcgcgcgcaacggagaccactgtccgctcgggcccgg gcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggct gggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatc ggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaa gacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcg tgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccggg gtgtcgctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:237) .

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:238.

II.H.36 DhMonoFc(N297G)-G₄-GDF15

The designation “DhMonoFc(N297G)-G4-GDF15” in the instant disclosure refers to a fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc(N297G) domain via a linker comprising the sequence of SEQ ID NO:58 that connects the N-terminus of the GDF 15 polypeptide to the C-terminus of the DhMonoFc(N297G) domain by a peptide bond.

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In certain embodiments, a homodimer is provided comprising two such fusion proteins linked via interchain disulfide bond between their respective GDF 15 polypeptides.

More particularly, in a specific embodiment, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (one each monomer) comprising the sequence 5 of SEQ IDNO:236;

(b) two GDF 15 polypeptides (one each monomer) comprising the sequence of SEQ ID NO: 12; and (c) two polypeptide linkers (one each monomer) comprising the sequence of SEQ ID NO:58 each linking the N-terminus of a GDF15 polypeptide to the C-terminus of a

DhMonoFc(N297G) domain by peptide bonds.

In a preferred embodiment, the fusion protein comprises the amino acid sequence (linker double underlined):

APEIIGGPSVFIFPPKPKDTIMI SRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVITVIHQDWINGKEYKCKVSNKAIPA

PIEKTISKAKGQPREPQVTTIPPSREEMTKNQVSITCIVKGFYPSDIAVE WESNGQPENNYDTTPPVIDSDGSFFIYSDITVDKSRWQQGNVFSCSVMHE AIHNHYTQKSISISPGOOOQARNGDHCPIGPGRCCRIHTVRASIEDIGWA DWVISPREVQVTMCIGACPSQFRAANMHAQIKTSIHRIKPDTVPAPCCVP ASYNPMVIIQKTDTGVSIQTYDDIIAKDCHCI (SEQ ID NO:240), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggaggtggtggagcgcgcaacggagaccactgtccgctcgggccc gggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctggg

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PCT/US2014/049254 ctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgca tcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatc aagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctg cgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccg gggtgtcgctccagacctatgatgacttgttagccaaagactgccactgc ata (SEQ ID NO:239) .

As discussed above, in a specific embodiment, a homodimer is provided comprising two monomers having the sequence of SEQ ID NO:240.

III. GDF15 Polypeptides and Constructs Comprising GDF15, Including Mutant

Forms Thereof

As disclosed herein, the GDF15 polypeptides (including the full length and mature forms of human GDF15) and the constructs comprising GDF15 described in the instant disclosure can be engineered and/or produced using standard molecular biology methodology to form a mutant form of the GDF15 polypeptides and constructs provided herein. In various examples, a nucleic acid sequence encoding a mutant form of the GDF15 polypeptides and constructs provided herein, which can comprise all or a portion of SEQ ID NOs:4, 8 or 12 can be isolated and/or amplified from genomic DNA, or cDNA using appropriate oligonucleotide primers. Primers can be designed based on the nucleic and amino acid sequences provided herein according to standard (RT)-PCR amplification techniques. The amplified GDF15 mutant polypeptide nucleic acid can then be cloned into a suitable vector and characterized by DNA sequence analysis.

Oligonucleotides for use as probes in isolating or amplifying all or a portion of a mutant form of the GDF15 polypeptides and constructs provided herein can be designed and generated using standard synthetic techniques, e.g., automated DNA synthesis apparatus, or can be isolated from a longer sequence of DNA.

III.A. GDF15 Polypeptide and Polynucleotide Sequences

In vivo, GDF15 is expressed as a contiguous amino acid sequence comprising a signal sequence, a pro domain and an active domain.

The 308 amino acid sequence of full length human GDF15 is:

MPGQELRTVNGSQMLLVLLVLSWLPHGGALSLAEASRASFPGPSELHSED

SRFRELRKRYEDLLTRLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGH

LHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARP

QAPALHLRLSPPPSQSDQLLAESSSARPQLELHLRPQAARGRRRARARNG

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DHCPIGPGRCCRIHTVRASIEDIGWADWVISPREVQVTMCIGACPSQFRA ANMHAQIKTSIHRIKPDTVPAPCCVPASYNPMVIIQKTDTGVSIQTYDDI LAKDCHCI (SEQ ID NO :4) and is encoded by the DNA sequence:

atgcccgggcaagaactcaggacggtgaatggctctcagatgctcctggt gttgctggtgctctcgtggctgccgcatgggggcgccctgtctctggccg aggcgagccgcgcaagtttcccgggaccctcagagttgcactccgaagac tccagattccgagagttgcggaaacgctacgaggacctgctaaccaggct gcgggccaaccagagctgggaagattcgaacaccgacctcgtcccggccc ctgcagtccggatactcacgccagaagtgcggctgggatccggcggccac ctgcacctgcgtatctctcgggccgcccttcccgaggggctccccgaggc ctcccgccttcaccgggctctgttccggctgtccccgacggcgtcaaggt cgtgggacgtgacacgaccgctgcggcgtcagctcagccttgcaagaccc caggcgcccgcgctgcacctgcgactgtcgccgccgccgtcgcagtcgga ccaactgctggcagaatcttcgtccgcacggccccagctggagttgcact tgcggccgcaagccgccagggggcgccgcagagcgcgtgcgcgcaacggg gaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccg cgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggg aggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcg gcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccga cacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgc tcattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttg ttagccaaagactgccactgcatatga (SEQ ID NO:3).

The 303 amino acid sequence of full length murine GDF15 is:

MAPPAIQAQPPGGSQIRFIIFIIIIIIIISWPSQGDAIAMPEQRPSGPES QINADEIRGRFQDIISRIHANQSREDSNSEPSPDPAVRIISPEVRIGSHG QIIIRVNRASISQGIPEAYRVHRAIIIITPTARPWDITRPIKRAISIRGP RAPAIRIRITPPPDIAMIPSGGTQIEIRIRVAAGRGRRSAHAHPRDSCPI GPGRCCHIETVQATIEDIGWSDWVISPRQIQISMCVGECPHIYRSANTHA

QIKARIHGIQPDKVPAPCCVPSSYTPVVIMHRTDSGVSIQTYDDIVARGC HCA (SEQ ID NO:6) and is encoded by the DNA sequence:

atggccccgcccgcgctccaggcccagcctccaggcggctctcaactgag gttcctgctgttcctgctgctgttgctgctgctgctgtcatggccatcgc agggggacgccctggcaatgcctgaacagcgaccctccggccctgagtcc

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PCT/US2014/049254 caactcaacgccgacgagctacggggtcgcttccaggacctgctgagccg gctgcatgccaaccagagccgagaggactcgaactcagaaccaagtcctg acccagctgtccggatactcagtccagaggtgagattggggtcccacggc cagctgctactccgcgtcaaccgggcgtcgctgagtcagggtctccccga agcctaccgcgtgcaccgagcgctgctcctgctgacgccgacggcccgcc cctgggacatcactaggcccctgaagcgtgcgctcagcctccggggaccc cgtgctcccgcattacgcctgcgcctgacgccgcctccggacctggctat gctgccctctggcggcacgcagctggaactgcgcttacgggtagccgccg gcagggggcgccgaagcgcgcatgcgcacccaagagactcgtgcccactg ggtccggggcgctgctgtcacttggagactgtgcaggcaactcttgaaga cttgggctggagcgactgggtgctgtccccgcgccagctgcagctgagca tgtgcgtgggcgagtgtccccacctgtatcgctccgcgaacacgcatgcg cagatcaaagcacgcctgcatggcctgcagcctgacaaggtgcctgcccc gtgctgtgtcccctccagctacaccccggtggttcttatgcacaggacag acagtggtgtgtcactgcagacttatgatgacctggtggcccggggctgc cactgcgcttga (SEQ ID NO:5).

The amino acid sequence of human GDF15 following cleavage of the 29 residue signal sequence is:

LSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTD

LVPAPAVRILTPEVRLGSGGHLHLRISRAALPEGLPEASRLHRALFRLSP

TASRSWDVTRPLRRQLSLARPQAPALHLRLSPPPSQSDQLLAESSSARPQ LELHLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWV LSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASY NPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO :8) and is encoded by the DNA sequence:

ctgtctctggccgaggcgagccgcgcaagtttcccgggaccctcagagtt gcactccgaagactccagattccgagagttgcggaaacgctacgaggacc tgctaaccaggctgcgggccaaccagagctgggaagattcgaacaccgac ctcgtcccggcccctgcagtccggatactcacgccagaagtgcggctggg atccggcggccacctgcacctgcgtatctctcgggccgcccttcccgagg ggctccccgaggcctcccgccttcaccgggctctgttccggctgtccccg acggcgtcaaggtcgtgggacgtgacacgaccgctgcggcgtcagctcag ccttgcaagaccccaggcgcccgcgctgcacctgcgactgtcgccgccgc cgtcgcagtcggaccaactgctggcagaatcttcgtccgcacggccccag ctggagttgcacttgcggccgcaagccgccagggggcgccgcagagcgcg

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PCT/US2014/049254 tgcgcgcaacggggaccactgtccgctcgggcccgggcgttgctgccgtc tgcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtg ctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgag ccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcacc gcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctac aatcccatggtgctcattcaaaagaccgacaccggggtgtcgctccagac ctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:7)

The amino acid sequence of murine GDF 15 following cleavage of the 32 residue signal sequence is:

SQGDALAMPEQRPSGPESQLNADELRGRFQDLLSRLHANQSREDSNSEPS PDPAVRILSPEVRLGSHGQLLLRVNRASLSQGLPEAYRVHRALLLLTPTA RPWDITRPLKRALSLRGPRAPALRLRLTPPPDLAMLPSGGTQLELRLRVA AGRGRRSAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQL SMCVGECPHLYRSANTHAQIKARLHGLQPDKVPAPCCVPSSYTPVVLMHR

TDSGVSLQTYDDLVARGCHCA (SEQ ID NO:10) and is encoded by the DNA sequence:

tcgcagggggacgccctggcaatgcctgaacagcgaccctccggccctga gtcccaactcaacgccgacgagctacggggtcgcttccaggacctgctga gccggctgcatgccaaccagagccgagaggactcgaactcagaaccaagt cctgacccagctgtccggatactcagtccagaggtgagattggggtccca cggccagctgctactccgcgtcaaccgggcgtcgctgagtcagggtctcc ccgaagcctaccgcgtgcaccgagcgctgctcctgctgacgccgacggcc cgcccctgggacatcactaggcccctgaagcgtgcgctcagcctccgggg accccgtgctcccgcattacgcctgcgcctgacgccgcctccggacctgg ctatgctgccctctggcggcacgcagctggaactgcgcttacgggtagcc gccggcagggggcgccgaagcgcgcatgcgcacccaagagactcgtgccc actgggtccggggcgctgctgtcacttggagactgtgcaggcaactcttg aagacttgggctggagcgactgggtgctgtccccgcgccagctgcagctg agcatgtgcgtgggcgagtgtccccacctgtatcgctccgcgaacacgca tgcgcagatcaaagcacgcctgcatggcctgcagcctgacaaggtgcctg ccccgtgctgtgtcccctccagctacaccccggtggttcttatgcacagg acagacagtggtgtgtcactgcagacttatgatgacctggtggcccgggg ctgccactgcgcttga (SEQ ID NO:9)

The biologically active form of GDF 15 comprises a homodimer comprising two mature GDF 15 monomers, each of which comprises SEQ ID NO: 12. The monomer that

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PCT/US2014/049254 homodimerizes to form the native mature human GDF 15 dimer is encoded by the nucleic acid sequence:

gcgcgcaacggggaccactgtccgctcgggcccgggcgttgctgccgtct gcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgc tgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagc cagttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccg cctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctaca atcccatggtgctcattcaaaagaccgacaccggggtgtcgctccagacc tatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:11) and comprises the amino acid sequence:

ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT YDDLLAKDCHCI (SEQ ID NO:12).

Thus, the “native mature human GDF 15 dimer” comprises two covalently associated 15 monomers comprising SEQ ID NO: 12.

The amino acid sequence of the recombinant active form of the human GDF 15, which comprises a homodimer comprising nine cysteines in each monomer to form one interchain disulfide bond and four intrachain disulfide bonds (shown with an optional N-terminal methionine residue in parentheses), is:

(M)ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGA

CPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVS LQTYDDLLAKDCHCI (SEQ ID NO:189) and is encoded by the DNA sequence (shown with an optional N-terminal methionine codon in parentheses):

(atg)gcgcgcaacggggaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcatataa (SEQ ID NO:190) .

The amino acid sequence of the recombinant active form of the murine

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GDF15, which comprises a homodimer comprising nine cysteines in each monomer to form one interchain disulfide bond and four intrachain disulfide bonds, is:

(M)SAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQLSMC VGECPHLYRSANTHAQIKARLHGLQPDKVPAPCCVPSSYTPVVLMHRTDS

GVSLQTYDDLVARGCHCA (SEQ ID NO:14) and is encoded by the DNA sequence:

(atg)agcgcgcatgcgcacccaagagactcgtgcccactgggtccgggg cgctgctgtcacctggagactgtgcaggcaactcttgaagacttgggctg gagcgactgggtgttgtccccgcgccagctgcagctgagcatgtgcgtgg gcgagtgtccccacctgtatcgctccgcgaacacgcatgcgcagatcaaa gcacgcctgcatggcctgcagcctgacaaggtgcctgccccgtgctgtgt cccctccagctacaccccggtggttcttatgcacaggacagacagtggtg tgtcactgcagacttatgatgacctggtggcccggggctgccactgcgct tga (SEQ ID NO:13).

As stated herein, the term “GDF15 polypeptide” refers to a GDF polypeptide comprising the human amino acid sequences SEQ ID NOs:4, 8 and 12. The term “GDF15 mutant polypeptide,” however, encompasses polypeptides comprising an amino acid sequence that differs from the amino acid sequence of a naturally-occurring GDF polypeptide sequence, e.g., SEQ ID NOs: 4, 8 and 12, by one or more amino acids, such that the sequence is at least

85% identical to SEQ ID NOs: 4, 8 and 12. GDF15 polypeptides can be generated by introducing one or more amino acid substitutions, either conservative or non-conservative and using naturally or non-naturally-occurring amino acids, at particular positions of the GDF 15 polypeptide, or by deleting particular residues or stretches of residues.

A “conservative amino acid substitution” can involve a substitution of a native amino acid residue (i.e., a residue found in a given position of the wild-type GDF15 polypeptide sequence) with a non-native residue (i.e., a residue that is not found in a given position of the wild-type GDF 15 polypeptide sequence) such that there is little or no effect on the polarity or charge of the amino acid residue at that position. Conservative amino acid substitutions also encompass non-naturally-occurring amino acid residues (as defined herein) that are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics, and other reversed or inverted forms of amino acid moieties.

Naturally-occurring residues can be divided into classes based on common side chain properties:

(1) hydrophobic: norleucine, Met, Ala, Val, Leu, lie;

(2) neutral hydrophilic: Cys, Ser, Thr;

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(4) basic: Asn, Gin, His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

Additional groups of amino acids can also be formulated using the principles described in, e.g., Creighton (1984) PROTEINS: STRUCTURE AND MOLECULAR PROPERTIES (2d Ed. 1993), W.H. Freeman and Company. In some instances it can be useful to further characterize substitutions based on two or more of such features (e.g., substitution with a “small polar’’ residue, such as a Thr residue, can represent a highly conservative substitution in an appropriate context).

Conservative substitutions can involve the exchange of a member of one of these classes for another member of the same class. Non-conservative substitutions can involve the exchange of a member of one of these classes for a member from another class.

Synthetic, rare, or modified amino acid residues having known similar 15 physiochemical properties to those of an above-described grouping can be used as a “conservative’’ substitute for a particular amino acid residue in a sequence. For example, a DArg residue may serve as a substitute for a typical L-Arg residue. It also can be the case that a particular substitution can be described in terms of two or more of the above described classes (e.g., a substitution with a small and hydrophobic residue means substituting one amino acid with a residue(s) that is found in both of the above-described classes or other synthetic, rare, or modified residues that are known in the art to have similar physiochemical properties to such residues meeting both definitions).

Nucleic acid sequences encoding a GDF15 mutant polypeptide provided herein, including those degenerate to SEQ ID NOs: 3, 7, 11 and 15, and those encoding polypeptide variants of SEQ ID NOs:4, 8 and 12, form other aspects of the instant disclosure.

III.B. Vectors Useful for Expressing GDF15 Polypeptides and Constructs Comprising

GDF15. Including Mutant Forms Thereof

In order to express the nucleic acid sequences encoding a polypeptide comprising a

GDF15 region, the appropriate coding sequences, e.g., SEQ ID NOs:3, 7 and 11, can be cloned into a suitable vector and after introduction in a suitable host, the sequence can be expressed to produce the encoded polypeptide according to standard cloning and expression techniques, which are known in the art (e.g., as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd, ed., Cold Spring Harbor

Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). The invention also relates to such vectors comprising a nucleic acid sequence according to the invention.

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A “vector” refers to a delivery vehicle that (a) promotes the expression of a polypeptide-encoding nucleic acid sequence; (b) promotes the production of the polypeptide therefrom; (c) promotes the transfection/transformation of target cells therewith; (d) promotes the replication of the nucleic acid sequence; (e) promotes stability of the nucleic acid; (f) promotes detection of the nucleic acid and/or transformed/transfected cells; and/or (g) otherwise imparts advantageous biological and/or physiochemical function to the polypeptide-encoding nucleic acid. A vector can be any suitable vector, including chromosomal, non-chromosomal, and synthetic nucleic acid vectors (a nucleic acid sequence comprising a suitable set of expression control elements). Examples of such vectors include derivatives of SV40, bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, and viral nucleic acid (RNA or DNA) vectors.

A recombinant expression vector can be designed for expression of a polypeptide comprising a GDF 15 region in prokaryotic (e.g., E. coli) or eukaryotic cells (e.g., insect cells, using baculovirus expression vectors, yeast cells, or mammalian cells). Representative host cells include those hosts typically used for cloning and expression, including Escherichia coli strains TOP10F', TOPIO, DH10B, DH5a, HB101, W3110, BL21(DE3) and BL21 (DE3)pLysS, BLUESCRIPT (Stratagene), mammalian cell lines CHO, CHO-K1, HEK293, 293-EBNA pIN vectors (Van Heeke & Schuster, J. Biol. Chem. 264: 5503-5509 (1989); pET vectors (Novagen, Madison Wis.). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase and an in vitro translation system. Preferably, the vector contains a promoter upstream of the cloning site containing the nucleic acid sequence encoding the polypeptide. Examples of promoters, which can be switched on and off, include the lac promoter, the T7 promoter, the trc promoter, the tac promoter and the trp promoter.

Thus, provided herein are vectors comprising a nucleic acid sequence encoding a polypeptide comprising a GDF 15 region that facilitate the expression of the polypeptide or construct of interest. In various embodiments, the vectors comprise an operably linked nucleotide sequence which regulates the expression of a polypeptide comprising a GDF 15 region. A vector can comprise or be associated with any suitable promoter, enhancer, and other expression-facilitating elements. Examples of such elements include strong expression promoters (e.g., a human CMV IE promoter/enhancer, an RSV promoter, SV40 promoter, SL3-3 promoter, MMTV promoter, or HIV LTR promoter, EFlalpha promoter, CAG promoter), effective poly (A) termination sequences, an origin of replication for plasmid product in E. coli, an antibiotic resistance gene as a selectable marker, and/or a convenient cloning site (e.g., a polylinker). Vectors also can comprise an inducible promoter as opposed to a constitutive promoter such as CMV IE. In one aspect, a nucleic acid comprising a

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III.C. Host Cells

In another aspect of the instant disclosure, host cells comprising the nucleic acids and vectors disclosed herein are provided. In various embodiments, the vector or nucleic acid is integrated into the host cell genome, which in other embodiments the vector or nucleic acid is extra-chromosomal.

Recombinant cells, such as yeast, bacterial (e.g., E. coli), and mammalian cells (e.g., immortalized mammalian cells) comprising such a nucleic acid, vector, or combinations of either or both thereof are provided. In various embodiments, cells comprising a nonintegrated nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression element, which comprises a sequence coding for expression of a polypeptide comprising a GDF 15 region.

A vector comprising a nucleic acid sequence encoding a polypeptide comprising a GDF 15 region can be introduced into a host cell by transformation or by transfection. Methods of transforming a cell with an expression vector are well known.

A nucleic acid encoding a polypeptide comprising a GDF 15 region can be positioned 20 in and/or delivered to a host cell or host animal via a viral vector. Any suitable viral vector can be used in this capacity. A viral vector can comprise any number of viral polynucleotides, alone or in combination with one or more viral proteins, which facilitate delivery, replication, and/or expression of the nucleic acid of the invention in a desired host cell. The viral vector can be a polynucleotide comprising all or part of a viral genome, a viral protein/nucleic acid conjugate, a virus-like particle (VTP), or an intact virus particle comprising viral nucleic acids and a nucleic acid encoding a polypeptide comprising a GDF 15 region. A viral particle viral vector can comprise a wild-type viral particle or a modified viral particle. The viral vector can be a vector which requires the presence of another vector or wild-type virus for replication and/or expression (e.g., a viral vector can be a helper-dependent virus), such as an adenoviral vector amplicon. Typically, such viral vectors consist of a wild-type viral particle, or a viral particle modified in its protein and/or nucleic acid content to increase transgene capacity or aid in transfection and/or expression of the nucleic acid (examples of such vectors include the herpes virus/AAV amplicons). Typically, a viral vector is similar to and/or derived from a virus that normally infects humans. Suitable viral vector particles in this respect, include, for example, adenoviral vector particles (including any virus of or derived from a virus of the adenoviridae), adeno-associated viral vector particles (AAV vector particles) or other parvoviruses and parvoviral vector particles, papillomaviral vector particles, flaviviral

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PCT/US2014/049254 vectors, alphaviral vectors, herpes viral vectors, pox virus vectors, retroviral vectors, including lentiviral vectors.

III. D. Isolation of a GDF15 Polypeptide, Construct Comprising a GDF15 Polypeptide or a

Mutant Form Thereof

A polypeptide comprising a GDF15 region can be isolated using standard protein purification methods. A polypeptide comprising a GDF15 region can be isolated from a cell that has been engineered to express a polypeptide comprising a GDF15 region, for example a cell that does not naturally express native GDF15.

Protein purification methods that can be employed to isolate polypeptide comprising a GDF15 region, as well as associated materials and reagents, are known in the art. Exemplary methods of purifying polypeptide comprising a GDF15 region are provided in the Examples herein below. Additional purification methods that may be useful for isolating polypeptide comprising a GDF15 region can be found in references such as Bootcov MR,

1997, Proc. Natl. Acad. Sci. USA 94:11514-9, Fairlie WD, 2000, Gene 254: 67-76.

IV. Pharmaceutical Compositions Comprising a GDF15 Polypeptide, Construct

Comprising a GDF15 Polypeptide or a Mutant Form Thereof

Pharmaceutical compositions comprising a monomer or multimer comprising a polypeptide comprising a GDF15 region are provided. Such polypeptide pharmaceutical compositions can comprise a therapeutically effective amount of a polypeptide comprising a monomer or multimer comprising a polypeptide comprising a GDF15 region in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration. The term “pharmaceutically acceptable carrier’’ or “physiologically acceptable carrier’’ as used herein refers to one or more formulation agents suitable for accomplishing or enhancing the delivery of a monomer or multimer comprising a polypeptide comprising a GDF15 region into the body of a human or non-human subject. The term includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In some cases it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in a pharmaceutical composition. Pharmaceutically acceptable substances such as wetting or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the monomer or multimer comprising a polypeptide comprising a GDF15 region can also act as, or form a component of, a carrier.

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Acceptable pharmaceutically acceptable carriers are preferably nontoxic to recipients at the dosages and concentrations employed.

A pharmaceutical composition can contain formulation agent(s) for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation agents include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as free serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as Polysorbate 20 or Polysorbate 80; Triton; tromethamine; lecithin; cholesterol or tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides - preferably sodium or potassium chloride - or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants (see, e.g.,

REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 19th edition, (1995); Berge et al., J. Pharm. Sci., 6661), 1-19 (1977). Additional relevant principles, methods, and agents are described in, e.g., Lieberman et al., PHARMACEUTICAL DOSAGE FORMSDISPERSE SYSTEMS (2nd ed., vol. 3, 1998); Ansel et al., PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS (7th ed. 2000); Martindale, THE EXTRA

PHARMACOPEIA (31 st edition), Remington's PHARMACEUTICAL SCIENCES (16111-20¹¹¹ and subsequent editions); The Pharmacological Basis Of Therapeutics, Goodman and Gilman, Eds. (9th ed.—1996); Wilson and Gisvolds’ TEXTBOOK OF ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY, Delgado and Remers, Eds. (10th ed., 1998). Principles of formulating pharmaceutically acceptable compositions also are described in, e.g., Aulton,

PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN, Churchill Livingstone (New York) (1988), EXTEMPORANEOUS ORAL LIQUID DOSAGE PREPARATIONS, CSHP (1998)).

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The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage (see, e.g., Remington's PHARMACEUTICAL SCIENCES, supra). Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a GDF 15 polypeptide, construct comprising a GDF 15 polypeptide or a mutant form thereof.

The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with free serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the present invention, compositions comprising a GDF 15 polypeptide, construct comprising a GDF 15 polypeptide or a mutant form thereof can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (Remington’s PHARMACEUTICAL SCIENCES, supra) in the form of a lyophilized cake or an aqueous solution. Furthermore, a product comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region can be formulated as a lyophilizate using appropriate excipients such as sucrose.

The polypeptide pharmaceutical compositions can be selected for parenteral delivery.

Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.

When parenteral administration is contemplated, the therapeutic compositions for use in this invention can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising a desired GDF 15 polypeptide, construct comprising a GDF 15 polypeptide or a mutant form thereof, in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a GDF 15 polypeptide, construct comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as

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PCT/US2014/049254 polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustained release of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.

In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a monomer or multimer comprising a polypeptide comprising a GDF 15 region can be formulated as a dry powder for inhalation. Inhalation solutions comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized. Pulmonary administration is further described in International Publication No. WO 94/20069, which describes the pulmonary delivery of chemically modified proteins.

It is also contemplated that certain formulations can be administered orally. In one embodiment of the present invention, a monomer or multimer comprising a polypeptide comprising a GDF 15 region that is administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of a monomer or multimer comprising a polypeptide comprising a GDF 15 region. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.

Another pharmaceutical composition can involve an effective quantity of a monomer or multimer comprising a polypeptide comprising a GDF 15 region in a mixture with non25 toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

Additional pharmaceutical compositions comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region will be evident to those skilled in the art, including formulations comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region, in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art (see, e.g., International Publication No. WO 93/15722, which describes

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PCT/US2014/049254 the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions, and Wischke & Schwendeman, 2008, Int. J. Pharm. 364: 298-327, and Freiberg & Zhu, 2004, Int. J. Pharm. 282: 1-18, which discuss microsphere/microparticle preparation and use). As described herein, a hydrogel is an example of a sustained- or controlled-delivery formulation.

Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides (U.S. Patent No. 3,773,919 and European Patent No. 0 058 481), copolymers of L-glutamic acid and gamma ethyl-L10 glutamate (Sidman et al., 1983, Biopolymers 22: 547-56), poly(2-hydroxyethyl-methacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15: 167-277 and Langer, 1982, Chem. Tech. 12: 98-105), ethylene vinyl acetate (Langer et al., supra) or poly-D(-)-3-hydroxybutyric acid (European Patent No. 0 133 988). Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art. See, e.g., Epstein et al.,

1985, Proc. Natl. Acad. Sci. U.S.A. 82: 3688-92; and European Patent Nos. 0 036 676, 0 088

046, and 0 143 949.

A pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region which is to be used for in vivo administration typically should be sterile. This can be accomplished by filtration through sterile filtration membranes. Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.

In a specific embodiment, the present invention is directed to kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this invention are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).

The effective amount of pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region which is to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One

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PCT/US2014/049254 skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which a monomer or multimer comprising a polypeptide comprising a GDF 15 region is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect. A typical dosage can range from about 0.1 pg/kg to up to about 100 mg/kg or more, depending on the factors mentioned above. In other embodiments, the dosage can range from 0.1 pg/kg up to about 100 mg/kg; or 1 pg/kg up to about 100 mg/kg; or 5 pg/kg, 10 pg/kg, 15 pg/kg, 20 pg/kg, 25 pg/kg, 30 pg/kg, 35 pg/kg, 40 pg/kg, 45 pg/kg, 50 pg/kg, 55 pg/kg, 60 pg/kg, 65 pg/kg, 70 pg/kg, 75 pg/kg, 100 pg/kg, 200 pg/kg or up to about 10 mg/kg.

The frequency of dosing will depend upon the pharmacokinetic parameters of the a monomer or multimer comprising a polypeptide comprising a GDF 15 region in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data.

The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems (which may also be injected);

or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.

Alternatively or additionally, the composition can be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.

In order to deliver drug, e.g., a monomer or multimer comprising a polypeptide comprising a GDF 15 region, at a predetermined rate such that the drug concentration can be maintained at a desired therapeutically effective level over an extended period, a variety of different approaches can be employed. In one example, a hydrogel comprising a polymer such as a gelatin (e.g., bovine gelatin, human gelatin, or gelatin from another source) or a

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PCT/US2014/049254 naturally-occurring or a synthetically generated polymer can be employed. Any percentage of polymer (e.g., gelatin) can be employed in a hydrogel, such as 5, 10, 15 or 20%. The selection of an appropriate concentration can depend on a variety of factors, such as the therapeutic profile desired and the pharmacokinetic profile of the therapeutic molecule.

Examples of polymers that can be incorporated into a hydrogel include polyethylene glycol (“PEG”), polyethylene oxide, polyethylene oxide-co-polypropylene oxide, copolyethylene oxide block or random copolymers, polyvinyl alcohol, poly(vinyl pyrrolidinone), poly(amino acids), dextran, heparin, polysaccharides, polyethers and the like.

Another factor that can be considered when generating a hydrogel formulation is the 10 degree of crosslinking in the hydrogel and the crosslinking agent. In one embodiment, crosslinking can be achieved via a methacrylation reaction involving methacrylic anhydride. In some situations, a high degree of cross-linking may be desirable while in other situations a lower degree of crosslinking is preferred. In some cases a higher degree of crosslinking provides a longer sustained release. A higher degree of crosslinking may provide a firmer hydrogel and a longer period over which drug is delivered.

Any ratio of polymer to crosslinking agent (e.g., methacrylic anhydride) can be employed to generate a hydrogel with desired properties. For example, the ratio of polymer to crosslinker can be, e.g., 8:1, 16:1, 24:1, or 32:1. For example, when the hydrogel polymer is gelatin and the crosslinker is methacrylate, ratios of 8:1, 16:1, 24:1, or 32:1 methyacrylic anhydride:gelatin can be employed.

V. Therapeutic Uses of a GDF15 Polypeptide, Construct Comprising a GDF15

Polypeptide or a Mutant Form Thereof

A monomer or multimer comprising a polypeptide comprising a GDF 15 region can 25 be used to treat, diagnose or ameliorate, a metabolic condition or disorder. In one embodiment, the metabolic disorder to be treated is diabetes, e.g., type 2 diabetes. In another embodiment, the metabolic condition or disorder is obesity. In other embodiments the metabolic condition or disorder is dyslipidemia, elevated glucose levels, elevated insulin levels or diabetic nephropathy. For example, a metabolic condition or disorder that can be treated or ameliorated using a monomer or multimer comprising a polypeptide comprising a GDF 15 region includes a state in which a human subject has a fasting blood glucose level of 125 mg/dL or greater, for example 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 or greater than 200 mg/dL. Blood glucose levels can be determined in the fed or fasted state, or at random. The metabolic condition or disorder can also comprise a condition in which a subject is at increased risk of developing a metabolic condition. For a human subject, such conditions include a fasting blood glucose level of 100 mg/dL. Conditions that can be treated using a pharmaceutical composition comprising a GDF 15

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PCT/US2014/049254 mutant polypeptide can also be found in the American Diabetes Association Standards of Medical Care in Diabetes Care-2011, American Diabetes Association, Diabetes Care Vol. 34, No. Supplement 1, S11-S61, 2010.

In application, a metabolic disorder or condition, such as Type 2 diabetes, elevated 5 glucose levels, elevated insulin levels, dyslipidemia, obesity or diabetic nephropathy, can be treated by administering a therapeutically effective dose of a GDF 15 polypeptide, construct comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region to a patient in need thereof. The administration can be performed as described herein, such as by IV injection, intraperitoneal (IP) injection, subcutaneous injection, intramuscular injection, or orally in the form of a tablet or liquid formation. In some situations, a therapeutically effective or preferred dose of a monomer or multimer comprising a polypeptide comprising a GDF 15 region can be determined by a clinician. A therapeutically effective dose of a monomer or multimer comprising a polypeptide comprising a GDF 15 region will depend, inter alia, upon the administration schedule, the unit dose of agent administered, whether the a monomer or multimer comprising a polypeptide comprising a GDF 15 region is administered in combination with other therapeutic agents, the immune status and the health of the recipient. The term “therapeutically effective dose,’’ as used herein, means an amount of a monomer or multimer comprising a polypeptide comprising a GDF 15 region that elicits a biological or medicinal response in a tissue system, animal, or human being sought by a researcher, medical doctor, or other clinician, which includes alleviation or amelioration of the symptoms of the disease or disorder being treated, i.e., an amount of a monomer or multimer comprising a polypeptide comprising a GDF 15 region that supports an observable level of one or more desired biological or medicinal response, for example, lowering blood glucose, insulin, triglyceride, or cholesterol levels; reducing body weight; or improving glucose tolerance, energy expenditure, or insulin sensitivity.

It is noted that a therapeutically effective dose of a monomer or multimer comprising a polypeptide comprising a GDF 15 region can also vary with the desired result. Thus, for example, in situations in which a lower level of blood glucose is indicated a dose of a monomer or multimer comprising a polypeptide comprising a GDF 15 region will be correspondingly higher than a dose in which a comparatively lower level of blood glucose is desired. Conversely, in situations in which a higher level of blood glucose is indicated at a dose of a monomer or multimer comprising a polypeptide comprising a GDF 15 region will be correspondingly lower than a dose in which a comparatively higher level of blood glucose is desired.

In various embodiments, a subject is a human having a blood glucose level of 100 mg/dL or greater can be treated with a monomer or multimer comprising a polypeptide comprising a GDF 15 region.

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In one embodiment, a method of the instant disclosure comprises first measuring a baseline level of one or more metabolically-relevant compounds such as glucose, insulin, cholesterol, lipid in a subject. A pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region is then administered to the subject. After a desired period of time, the level of the one or more metabolically-relevant compounds (e.g., blood glucose, insulin, cholesterol, lipid) in the subject is again measured. The two levels can then be compared in order to determine the relative change in the metabolically-relevant compound in the subject. Depending on the outcome of that comparison another dose of the pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region can be administered to achieve a desired level of one or more metabolically-relevant compound.

It is noted that a pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region can be co-administered with another compound. The identity and properties of compound co-administered with the a monomer or multimer comprising a polypeptide comprising a GDF 15 region will depend on the nature of the condition to be treated or ameliorated. A non-limiting list of examples of compounds that can be administered in combination with a pharmaceutical composition comprising a monomer or multimer comprising a polypeptide comprising a GDF 15 region include rosiglitizone, pioglitizone, repaglinide, nateglitinide, metformin, exenatide, stiagliptin, pramlintide, glipizide, glimeprirideacarbose, and miglitol.

VI. Kits

Also provided are kits for practicing the disclosed methods. Such kits can comprise a pharmaceutical composition such as those described herein, including nucleic acids encoding the peptides or proteins provided herein, vectors and cells comprising such nucleic acids, and pharmaceutical compositions comprising such nucleic acid-containing compounds, which can be provided in a sterile container. Optionally, instructions on how to employ the provided pharmaceutical composition in the treatment of a metabolic disorder can also be included or be made available to a patient or a medical service provider.

In one aspect, a kit comprises (a) a pharmaceutical composition comprising a therapeutically effective amount of a monomer or multimer comprising a polypeptide comprising a GDF 15 region; and (b) one or more containers for the pharmaceutical composition. Such a kit can also comprise instructions for the use thereof; the instructions can be tailored to the precise metabolic disorder being treated. The instructions can describe the use and nature of the materials provided in the kit. In certain embodiments, kits include instructions for a patient to carry out administration to treat a metabolic disorder, such as

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PCT/US2014/049254 elevated glucose levels, elevated insulin levels, obesity, type 2 diabetes, dyslipidemia or diabetic nephropathy.

Instructions can be printed on a substrate, such as paper or plastic, etc, and can be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (e.g., associated with the packaging), etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, such as over the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded.

Often it will be desirable that some or all components of a kit are packaged in suitable packaging to maintain sterility. The components of a kit can be packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.

EXAMPLES

The following examples, including the experiments conducted and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention.

EXAMPLE 1

Preparation of Fc-GDF15 Molecules

GDF 15 fusions with knob/holeFc, HemiFc, charged pair (delHinge) Fc and charged 25 pair (delHinge) cysteine clamp Fc sequences were stably expressed in serum free, suspension adapted CHO-K1 cell line. GDF15-Fc molecules were cloned into a stable expression vector containing puromycin resistance while the Fc chains were cloned into a hygromycin containing expression vector (Selexis, Inc.). The plasmids were transfected at a 1:1 ratio using lipofectamine LTX and cells were selected 2 days post transfection in a proprietary growth media containing lOug/mL puromycin and 600ug/mLhygromycin. Media was exchanged 2 times per week during selection. When cells reached about 90% viability, they were scaled up for a fedbatch production run. Cells were seeded at 1 e6/mL in a proprietary production media and fed on days 3, 6, and 8. The conditioned medium (CM) produced by the cells was harvested on day 10 and clarified. Endpoint viabilities typically were above 90%.

The Fc-GDF15 clarified, conditioned media was purified using a two-step chromatography procedure. Approximately 5 L of the CM was applied directly to a GE MabSelect SuRe column that had previously been equilibrated with Dulbecco’s Phosphate

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Buffered Saline (PBS). The bound protein underwent three wash steps: first, 3 column volumes (CV) of PBS; next, 1 CV of 20 mM Tris, 100 mM sodium chloride, pH 7.4; and finally, 3 CV of 500 mM L-arginine, pH 7.5. These wash steps remove unbound or lightly bound media components and host cell impurities. The column was then re-equilibrated with

5 CV of 20 mM Tris, 100 mM sodium chloride at pH 7.4 which brings the UV absorbance back to baseline. The desired protein was eluted with 100 mM acetic acid at pH 3.6 and collected in bulk. The protein pool was quickly titrated to within a pH range of 5.0 to 5.5 with 1 M Tris-HCl, pH 9.2.

The pH adjusted protein pool was next loaded onto a GE SP Sepharose HP column 10 that had been previously equilibrated with 20 mM MES at pH 6.0. The bound protein was then washed with 5 CV of equilibration buffer, and finally eluted over a 20 CV, 0 to 50% linear gradient from 0 to 400 mM sodium chloride in 20 mM MES at pH 6.0. Fractions were collected during the elution and analyzed by analytical size-exclusion chromatography (Superdex 200) to determine the appropriate fractions to pool for a homogeneous product.

The SP HP chromatography removes product-related impurities such as free Fc, clipped species, and Fc-GDF15 multimers.

The SP HP pool was then buffer exchanged into 10 mM sodium acetate, 5% proline, pH 5.2 by dialysis. It was concentrated to approximately 15 mg/ml using the Sartorius Vivaspin 20 Ten kilo-Dalton molecular weight cut-off centrifugal device. Finally, it was sterile filtered and the resulting solution containing the purified Fc-GDF15 molecules is stored at 5° C. Final products were assessed for identity and purity using mass spectral analysis, sodium dodecyl sulfate polyacrylamide electrophoresis and size exclusion high performance liquid chromatography.

The purification method described above was employed to purify DhMonoFc-GDF15 fusion proteins. However, it was found that the addition of the H6D mutation to the DhMonoFc-GDF15 caused soluble aggregates to form in the SP elution. Therefore, the purification of the DhMonoFc-GFF15(H6D) included an additional SEC step (Superdex 200 with 20 mM phosphate, 250 mM NaCl, pH 6.8), followed by loading on Q-sepharose HP and eluting with a gradient from 0 to 0.6M NaCl in 20 mM tris, pH 8.5.

EXAMPLE 2

Preparation of GDF15-HSA and DhMonoFc Molecules

GDF15 fusions with HSA and DhMonoFc sequences were stably expressed in CHOS cells (Invitrogen). For each of the constructs producing homodimers, the coding sequence was cloned into stable expression vector containing puromycin resistance (Selexis, Inc.). In the case of the HSA-(G4S)4-GDF15:GDF15 heterodimer, the HSA-(G4S)4-GDF15 fusion sequence was cloned into an expression vector containing puromycin resistance and the

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GDF15 sequence was cloned into an expression vector containing hygromycin resistance.

CHO-S parental cells were maintained in CD-CHO medium (Invitrogen) supplemented with 8 mM L-glutamine and were transfected with 4pg of plasmid DNA using a Lipofectamine LTX transfection kit (Invitrogen) according to the manufacturer’s instructions. In the case of the

HSA-(G4S)4-GDF15:GDF15 heterodimer, the two plasmids were mixed at a 1:1 ratio prior to transfection. Stable cell lines were selected using 10 μ g/mL of puromycin (homodimers) or 10 μ g/mL of puromycin plus 400 μ g/mL hygromicin (heterodimer). Upon recovery, which was defined as >90% viability using a Vi-Cell counter (Beckman Coulter), the stable CHO-S cell lines were expanded and used to seed either batch productions in shake flasks or fedbatch productions in WAVE bioreactors (GE Healthcare). Both processes were seeded at le6 viable cells/mL in production medium. Batch productions were harvested by centrifugation on day 6, while fedbatch productions were fed on days 3, 6, and 8. The CM produced by the cells was harvested by centrifugation on day 10 and clarified.

The HSA-GDF15 fusion proteins were purified from clarified conditioned media using two chromatographic steps. The clarified conditioned media containing the HSAGDF15 fusion protein was applied to a Cibracon Blue Sepharose HP column that is equilibrated with 20mM Phosphate, 150mM NaCl pH 7.4. The column was next washed with equilibration buffer until a baseline ultraviolet (UV) level is obtained. Product and contaminants are eluted by a 20 mM Phosphate, 2M NaCl buffer and the elutions were collected and subsequently assayed by Coomasie-stained SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) to identify which eluate fractions contained a polypeptide that migrates at the predicted molecular weight of HSA-GDF15 fusion protein. Following the Blue Sepharose step, the pooled fractions containing product were dialyzed versus 10 mM tris, pH 8.0. The dialysis step allowed for the binding of HSA-GDF15 fusion protein when applied to anion exchange chromatographic resin. The final chromatography step was QSepharose HP which applies a linear gradient (0 to 0.6M NaCl in 10 mM tris pH 8.0) to elute the bound fusion protein. The elution from the Q-Sepharose HP was collected as fractions and then assayed by SDS-PAGE and analytical size exclusion chromatography to determine the appropriate fractions to pool. LCMS and SDS-PAGE were run to confirm the identity of each protein. The resulting pool was buffer exchanged by dialysis into 1 OmM Sodium Acetate, 9% sucrose pH 4.5, sterile filtered, and finally stored at 5 C or frozen.

DhMonoFc-GDF15 fusion proteins were purified as set forth above in Example 2 for other Fc-GDF 15 fusion proteins.

EXAMPLE 3

Suppression of Food Intake in Hyperphagic ob/ob Mice by Fc Fusion GDF15 Polypeptides and HSA Fusion GDF15 Polypeptides

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GDF15 reduces food intake in hyperphagic ob/ob mice, and a food intake assay was used to evaluate efficacy of different forms of GDF15 analogs. As the half-life of human

GDF15 polypeptide in mouse was observed to be approximately 3 hours, an Fe fusion strategy was used to extend protein half-life. Various multimers comprising a polypeptide comprising a GDF15 region were generated and analyzed for in vivo activity, by introducing the multimer into hyperphagic leptin-deficient ob/ob mice, and measuring the ability of a particular multimer comprising a polypeptide comprising a GDF15 region to suppress food intake in these animals. The multimer comprising a polypeptide comprising a GDF15 region to be tested was injected subcutaneously into a 7-8 week old ob/ob mouse (Jackson

Laboratory) between 4-5pm on day 0. Animals were transferred after injection to cages where food had been premeasured, and food intake was measured between 9-10 AM the next day.

The results of representative experiments are provided in Figures 6-53. These experiments demonstrate that the described multimers comprising GDF15 regions exhibit a decrease in food intake in ob/ob mice, with greater potency than those of native mature hGDF 15 homodimer.

EXAMPLE 4

Chronic Efficacy of GDF15 Constructs in DIO Mice

Certain multimers comprising GDF15 regions are administered chronically and 20 subcutaneously into DIO mice, once per week. The constructs demonstrate efficacy in improving various metabolic parameters, including body weight, blood glucose levels and glucose tolerance, serum insulin levels, serum cholesterol levels, serum triglyceride levels and oral lipid tolerance.

EXAMPLE 5

In Vivo Activity of GDF15 Constructs

Male C57B1/6 were fed a 60% high fat diet for 15 weeks and divided into different treatment groups for each group to have the same pretreatment body weight, glucose, insulin, triglyceride and cholesterol levels. Animals were subcutaneously dosed with proteins or vehicle buffer weekly for 5 weeks. Three different dose levels were selected for the proteins: 10, 1, O.lnmol/kg, which are equivalent to 1.25, 0.125, 0.0125 mg/kg. Studies were carried for 5 weeks, with the last dose on day 28.

Body weight was measured weekly during the 5 weeks of treatment and drug washout. One oral glucose tolerance tests (OGTT) was performed 2 weeks after the first protein injection in animals fasted for 4 hours. Another oral glucose tolerance tests (OGTT) was performed 5 weeks after the first protein injection in animals fasted for 16 hours. In OGTT, animals were orally administered with 2g/kg glucose solution, and glucose levels

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PCT/US2014/049254 were measured by AlphaTRAK glucometer (Abbott) at 0, 15, 30, 60, 120min. Area under the curve (AUC) of the glucose levels during the OGTT were calculated to compare glucose tolerance of different treatment groups. Serum samples were collected at 3 weeks after first protein injection and used to measure insulin, triglyceride and cholesterol levels, as well as the levels of test articles. Insulin levels were measured using immunoassay kit (Alpco). Triglyceride and cholesterol levels were measured using enzymatic assays (Wako).

The results are shown in Figures 54-59 (asterisks indicate statistical significance). These experiments demonstrate that the described multimers comprising GDF15 regions reduce AUC of the glucose levels during the OGTT (Figures 55 and 59), reduce body weight (Figure 54) reduce insulin levels (Figure 56), reduce cholesterol (Figure 58) and reduce triglycerides (Figure 57).

EXAMPLE 6

Thermal Stability of GDF15 Constructs

The thermal stability of the selected GDF15 constructs was assessed by differential scanning calorimetry on a MicroCal Capillary VP-DSC system in which temperature differences between the reference and sample cell are continuously measured, and calibrated to power units. This data channel is referred to as the DP signal, or the differential power between the reference and sample cell. The unfolding of a protein molecule appears as an endothermic transition on the DSC thermogram and can characterized by the thermal transition midpoints (Tm). The samples were heated from 10°C to 100°C at a heating rate of 60°C/hour. The pre-scan time was 15 minutes and the filtering period was 10 seconds. The concentrations used in the DSC experiments were around 1.0 mg/mL. The data analysis for baseline correction and determination of Tm values was done using MicroCal Origin 7 software.

In particular, a dimer of DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) was compared to a dimer of Dh3CpmFc(-)-GDF15(N3D):DhCpmFc(+); a dimer of DhCpmFc(-)GDF15(Ndel3):DhCpmFc(+) was compared to a dimer of Dh3CpmFc(-)GDF15(Ndel3):DhCpmFc(+); a dimer of DhCpmFc(-)(Y349C)30 GDF15(N3D):DhCpmFc(+)(S354C) was compared to a dimer of Dh3CpmFc(-)(Y349C)GDF15(N3D):DhCpmFc(+)(S354C); and a dimer of DhCpmFc(-)(Y349C)GDF15(Ndel3):DhCpmFc(+)(S354C) was compared to a dimer of Dh3CpmFc(-)(Y349C)GDF15(Ndel3):DhCpmFc(+)(S354C). The results are shown in Figure 61. These experiments demonstrate that the “Dh3CpmFc” domains confer greater stability than the corresponding “DhCpmFc” domains.

EXAMPLE 7

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Fcv Receptor Binding Analysis

Selected GDF 15 constructs were analyzed for their binding activity to Fey receptors on BIA3000. Each Fey receptor was captured on anti-his antibody coated CM5 surface (captured RL ~ 200 RU). The GDF 15 constructs were diluted to 250 nM in sample buffer (0.1 mg/ml BSA, 0.005% P20, PBS). Each GDF15 construct was injected over anti-his antibody captured Fey receptor surfaces at 50 μΤ/min for 3 minutes. After a 5-minute dissociation in instrument running buffer (0.005% P20 in PBS), each Fey receptor surface was regenerated by an injection of 8 mM Glycine, pHl .5, 1M NaCI for 30 seconds, followed by an injection of 10 mM Glycine, pH1.5 for 30 seconds. The resulting sensorgrams were analyzed using BIAcore BIAEvaluation (v. 4.1). The binding response in the unit of RU was read at 10 seconds before end of injection.

In particular, FcyRI, FcyRIIIA and FcyRIIA were determined with respect to a dimer of DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+),a dimer of DhCpmFc(-)(Y349C)GDF15(Ndel3): DhCpmFc(+)(S354C); a dimer of Dh3CpmFc(-)-GDF15(Ndel3); a dimer of

Dh3CpmFc(-)(Y349C)-GDF15(Ndel3)-Dh3CpmFc(+)(S354C); a dimer of Dh3CpmFc(-)GDF15(N3D); and a dimer of Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C). The results are shown in Figure 60. These experiments demonstrate that the “Dh3CpmFc” domains essentially eliminate FcyRI, FcyRIIIA and FcyRIIA binding.

While the present invention has been described in terms of various embodiments, it is understood that variations and modifications will occur to those skilled in the art. Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the invention as claimed. In addition, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

All references cited in this application are expressly incorporated by reference herein for any purpose.

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Claims (38)

1. A fusion protein comprising a GDF 15 region and an Fc domain, wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 220 and wherein the N-terminus of the Fc

5 domain consists of residues 1 to 210 of SEQ ID NO: 220.

2. A fusion protein comprising a GDF 15 region and an Fc domain,, wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 227 and wherein the N-terminus of the Fc domain consists of residues 1 to 210 of SEQ ID NO: 227.

3. The fusion protein of claim 1 or claim 2, wherein the GDF 15 region comprises an amino

0 acid sequence of SEQ ID NO: 4, 8, 12, 25, 52 or 55.

4. The fusion protein of claim 3, wherein the Fc domain and GDF15 amino acid sequences correspond to amino acid sequences of SEQ ID NO: 222, 225, 229, or 232.

5. The fusion protein of any one of the preceding claims, further wherein the GDF 15 region and the Fc domain are joined by a polypeptide linker.

5

6. The fusion protein of claim 5, wherein the polypeptide linker comprises an amino acid sequence of SEQ ID NO: 18,30, 34, 40,58,61,64, 69, 72, 75,78, 113, 116, 119, 122, 125, or 128.

7. The fusion protein of any one of the preceding claims, further comprising an N-terminal VK1 signal sequence.

20 8. The fusion protein of any one of the preceding claims, wherein the GDF 15 region comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 4,

8. or 12.

9. The fusion protein of claim 8, wherein the GDF 15 region comprises an amino acid sequence that is at least about 85 percent identical to SEQ ID NO: 12 and comprises a mutation

25 at position 3.

10. The fusion protein of claim 9, wherein the mutation at position 3 is a N3Q mutation.

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11. A dimer comprising (i) a first protein comprising a fusion protein of any one of claims 1 to 7, and (ii) a second protein comprising an Fc domain.

12. The dimer of claim 11, wherein the second protein comprises an amino acid sequence of SEQ ID NO: 219, 226, 301, or 302.

5

13. The dimer of claim 11 or claim 12, wherein the first protein and the second protein are nontocovalently associated.

14. The dimer of claim 11 or claim 12, wherein the first protein and the second protein are covalently associated.

15. The dimer of claim 11 or claim 12, wherein the first protein and the second protein are 0 associated via a disulfide bond.

16. A tetramer comprising (a) a first dimer of any one of claims 1 Ito 15 and (b) a second dimer of any one of claims 11 to 15.

17. The tetramer of claim 16, wherein the first dimer and the second dimer are non-covalently associated.

5

18. The tetramer of claim 16, wherein the first dimer and the second dimer are covalently associated.

19. The tetramer of claim 16, wherein the first dimer and the second dimer are associated via a disulfide bond.

20. The tetramer of claim 19, wherein the first dimer and the second dimer are associated 20 via an interchain disulfide bond between a GDF 15 region of the first dimer and a GDF 15 region of the second dimer.

21. A method of treating a metabolic disorder in a subject characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels which comprises administering to the subject an effective amount of a fusion protein of any one of

25 claims 1 to 10.

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22. A method of treating diabetes, obesity, dyslipidemia or diabetic nephropathy in a subject comprising administering to the subject an effective amount of a fusion protein of any one of claims 1 to 10.

23. A method of treatment to reduce food intake, body weight, insulin levels, triglyceride 5 levels, cholesterol levels or glucose levels in a subject which comprises administering to the subject an effective amount of a fusion protein of any one of claims 1 to 10.

24. A method of treating a metabolic disorder in a subject characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels which comprises administering to the subject an effective amount of a dimer of any one of claims 11

0 to 15.

25. A method of treating diabetes, obesity, dyslipidemia or diabetic nephropathy in a subject comprising administering to the subject an effective amount of a dimer of any one of claims 11 to 15.

26. A method of treatment to reduce food intake, body weight, insulin levels, triglyceride 5 levels, cholesterol levels or glucose levels in a subject which comprises administering to the subject an effective amount of a dimer of any one of claims 11 to 15.

27. A method of treating a metabolic disorder in a subject characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels which comprises administering to the subject an effective amount of a tetramer of any one of claims

20 16 to 20.

28. A method of treating diabetes, obesity, dyslipidemia or diabetic nephropathy in a subject comprising administering to the subject an effective amount of a tetramer of any one of claims 16 to 20.

29. A method of treatment to reduce food intake, body weight, insulin levels, triglyceride 25 levels, cholesterol levels or glucose levels in a subject which comprises administering to the subject an effective amount of tetramer of any one of claims 16 to 20.

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30. Use of a fusion protein of any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels.

31. Use of the fusion protein of any one of claims 1 to 10 in the manufacture of a

5 medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

32. Use of a fusion protein of any one of claims 1 to 10 in the manufacture of a medicament for reducing: food intake; body weight; insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

33. Use of a dimer of any one of claims 11 to 15 in the manufacture of a medicament for the 0 treatment of a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels.

34. Use of the dimer of any one of claims 11 to 15 in the manufacture of a medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

35. Use of a dimer of any one of claims 11 to 15 in the manufacture of a medicament for 5 reducing: food intake; body weight; insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

36. Use of a tetramer of any one of claims 16 to 20 in the manufacture of a medicament for the treatment of a metabolic disorder characterised by increased body weight or food intake, or elevated insulin, triglyceride, cholesterol or glucose levels.

20

37. Use of the tetramer of any one of claims 16 to 20 in the manufacture of a medicament for the treatment of diabetes, obesity, dyslipidemia or diabetic nephropathy.

38. Use of a tetramer of any one of claims 16 to 20 in the manufacture of a medicament for reducing: food intake; body weight; insulin levels; triglyceride levels; cholesterol levels; or glucose levels.

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A-1850-WO-PCT_SL.txt SEQUENCE LISTING <110> AMGEN INC.

<120> GROWTH DIFFERENTIATION FACTOR 15 (GDF-15) CONSTRUCTS <130> A-1850-WO-PCT <140> <141> <150> 61/860,723 <151> 2013-07-31 <160> 305 <170> PatentIn version 3.5 <210> 1 <211> 4 <212> PRT <213> Artificial Sequence <220> <221> source <223> /note=Description of Artificial Sequence: Synthetic

peptide <400> 1

Arg Gly Arg Arg 1 <210> 2 <211> 7 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 2

Arg Gly Arg Arg Arg Ala Arg

1 5 <210> 3 <211> 927 <212> DNA <213> Homo sapiens <400> 3

atgcccgggc aagaactcag gacggtgaat ggctctcaga tgctcctggt gttgctggtg 60 ctctcgtggc tgccgcatgg gggcgccctg tctctggccg aggcgagccg cgcaagtttc 120 ccgggaccct cagagttgca ctccgaagac tccagattcc gagagttgcg gaaacgctac 180 gaggacctgc taaccaggct gcgggccaac cagagctggg aagattcgaa caccgacctc 240 gtcccggccc ctgcagtccg gatactcacg ccagaagtgc ggctgggatc cggcggccac 300 ctgcacctgc gtatctctcg ggccgccctt cccgaggggc tccccgaggc ctcccgcctt 360 caccgggctc tgttccggct gtccccgacg gcgtcaaggt cgtgggacgt gacacgaccg 420

Page 1

ctgcggcgtc agctcagcct A-: tgcaagaccc 1850-WO-PCT. caggcgcccg _SL.txt cgctgcacct gcgactgtcg 480 ccgccgccgt cgcagtcgga ccaactgctg gcagaatctt cgtccgcacg gccccagctg 540 gagttgcact tgcggccgca agccgccagg gggcgccgca gagcgcgtgc gcgcaacggg 600 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 660 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 720 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 780 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 840 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 900 ttagccaaag actgccactg catatga 927

<210> 4 <211> 308 <212> PRT <213> Homo sapiens <400> 4

Met 1 Pro Gly Gln Glu 5 Leu Arg Thr Val Asn Gly Ser 10 Gln Met Leu 15 Leu Val Leu Leu Val Leu Ser Trp Leu Pro His Gly Gly Ala Leu Ser Leu 20 25 30 Ala Glu Ala Ser Arg Ala Ser Phe Pro Gly Pro Ser Glu Leu His Ser 35 40 45 Glu Asp Ser Arg Phe Arg Glu Leu Arg Lys Arg Tyr Glu Asp Leu Leu 50 55 60 Thr Arg Leu Arg Ala Asn Gln Ser Trp Glu Asp Ser Asn Thr Asp Leu 65 70 75 80 Val Pro Ala Pro Ala Val Arg Ile Leu Thr Pro Glu Val Arg Leu Gly 85 90 95 Ser Gly Gly His Leu His Leu Arg Ile Ser Arg Ala Ala Leu Pro Glu 100 105 110 Gly Leu Pro Glu Ala Ser Arg Leu His Arg Ala Leu Phe Arg Leu Ser 115 120 125 Pro Thr Ala Ser Arg Ser Trp Asp Val Thr Arg Pro Leu Arg Arg Gln 130 135 140 Leu Ser Leu Ala Arg Pro Gln Ala Pro Ala Leu His Leu Arg Leu Ser 145 150 155 160 Pro Pro Pro Ser Gln Ser Asp Gln Leu Leu Ala Glu Ser Ser Ser Ala 165 170 175

Page 2

A-1850-WO-PCT_SL.txt

Arg Pro Gln Leu 180 Glu Leu His Leu Arg 185 Pro Gln Ala Ala Arg Gly Arg 190 Arg Arg Ala Arg Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly 195 200 205 Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly 210 215 220 Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys 225 230 235 240 Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln 245 250 255 Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro 260 265 270 Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr 275 280 285 Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp 290 295 300

Cys His Cys Ile 305 <210> 5 <211> 912 <212> DNA <213> Mus sp. <400> 5

atggccccgc ccgcgctcca ggcccagcct ccaggcggct ctcaactgag gttcctgctg 60 ttcctgctgc tgttgctgct gctgctgtca tggccatcgc agggggacgc cctggcaatg 120 cctgaacagc gaccctccgg ccctgagtcc caactcaacg ccgacgagct acggggtcgc 180 ttccaggacc tgctgagccg gctgcatgcc aaccagagcc gagaggactc gaactcagaa 240 ccaagtcctg acccagctgt ccggatactc agtccagagg tgagattggg gtcccacggc 300 cagctgctac tccgcgtcaa ccgggcgtcg ctgagtcagg gtctccccga agcctaccgc 360 gtgcaccgag cgctgctcct gctgacgccg acggcccgcc cctgggacat cactaggccc 420 ctgaagcgtg cgctcagcct ccggggaccc cgtgctcccg cattacgcct gcgcctgacg 480 ccgcctccgg acctggctat gctgccctct ggcggcacgc agctggaact gcgcttacgg 540 gtagccgccg gcagggggcg ccgaagcgcg catgcgcacc caagagactc gtgcccactg 600 ggtccggggc gctgctgtca cttggagact gtgcaggcaa ctcttgaaga cttgggctgg 660 agcgactggg tgctgtcccc gcgccagctg cagctgagca tgtgcgtggg cgagtgtccc 720 cacctgtatc gctccgcgaa cacgcatgcg cagatcaaag Page 3 cacgcctgca tggcctgcag 780

A-1850-WO-PCT_SL.txt cctgacaagg tgcctgcccc gtgctgtgtc ccctccagct acaccccggt ggttcttatg cacaggacag acagtggtgt gtcactgcag acttatgatg acctggtggc ccggggctgc cactgcgctt ga

840

900

912 <210> 6 <211> 303 <212> PRT <213> Mus sp.

<400> 6 Gly Gly Ser Gln 15 Leu Met 1 Ala Pro Pro Ala 5 Leu Gln Ala Gln Pro 10 Pro Arg Phe Leu Leu Phe Leu Leu Leu Leu Leu Leu Leu Leu Ser Trp Pro 20 25 30 Ser Gln Gly Asp Ala Leu Ala Met Pro Glu Gln Arg Pro Ser Gly Pro 35 40 45 Glu Ser Gln Leu Asn Ala Asp Glu Leu Arg Gly Arg Phe Gln Asp Leu 50 55 60 Leu Ser Arg Leu His Ala Asn Gln Ser Arg Glu Asp Ser Asn Ser Glu 65 70 75 80 Pro Ser Pro Asp Pro Ala Val Arg Ile Leu Ser Pro Glu Val Arg Leu 85 90 95 Gly Ser His Gly Gln Leu Leu Leu Arg Val Asn Arg Ala Ser Leu Ser 100 105 110 Gln Gly Leu Pro Glu Ala Tyr Arg Val His Arg Ala Leu Leu Leu Leu 115 120 125 Thr Pro Thr Ala Arg Pro Trp Asp Ile Thr Arg Pro Leu Lys Arg Ala 130 135 140 Leu Ser Leu Arg Gly Pro Arg Ala Pro Ala Leu Arg Leu Arg Leu Thr 145 150 155 160 Pro Pro Pro Asp Leu Ala Met Leu Pro Ser Gly Gly Thr Gln Leu Glu 165 170 175 Leu Arg Leu Arg Val Ala Ala Gly Arg Gly Arg Arg Ser Ala His Ala 180 185 190 His Pro Arg Asp Ser Cys Pro Leu Gly Pro Gly Arg Cys Cys His Leu 195 200 205 Glu Thr Val Gln Ala Thr Leu Glu Asp Leu Gly Trp Ser Asp Trp Val 210 215 220

Page 4

A-1850-WO-PCT_SL.txt

Leu Ser Pro Arg Gln Leu Gln Leu Ser Met Cys Val Gly Glu Cys Pro 225 230 235 240 His Leu Tyr Arg Ser Ala Asn Thr His Ala Gln Ile Lys Ala Arg Leu 245 250 255 His Gly Leu Gln Pro Asp Lys Val Pro Ala Pro Cys Cys Val Pro Ser 260 265 270 Ser Tyr Thr Pro Val Val Leu Met His Arg Thr Asp Ser Gly Val Ser 275 280 285 Leu Gln Thr Tyr Asp Asp Leu Val Ala Arg Gly Cys His Cys Ala 290 295 300

<210> 7 <211> 840 <212> DNA <213> Homo sapiens <400> 7

ctgtctctgg ccgaggcgag ccgcgcaagt ttcccgggac cctcagagtt gcactccgaa 60 gactccagat tccgagagtt gcggaaacgc tacgaggacc tgctaaccag gctgcgggcc 120 aaccagagct gggaagattc gaacaccgac ctcgtcccgg cccctgcagt ccggatactc 180 acgccagaag tgcggctggg atccggcggc cacctgcacc tgcgtatctc tcgggccgcc 240 cttcccgagg ggctccccga ggcctcccgc cttcaccggg ctctgttccg gctgtccccg 300 acggcgtcaa ggtcgtggga cgtgacacga ccgctgcggc gtcagctcag ccttgcaaga 360 ccccaggcgc ccgcgctgca cctgcgactg tcgccgccgc cgtcgcagtc ggaccaactg 420 ctggcagaat cttcgtccgc acggccccag ctggagttgc acttgcggcc gcaagccgcc 480 agggggcgcc gcagagcgcg tgcgcgcaac ggggaccact gtccgctcgg gcccgggcgt 540 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 600 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 660 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 720 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 780 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcatatga 840

<210> 8 <211> 279 <212> PRT <213> Homo sapiens <400> 8

Leu Ser Leu Ala Glu Ala Ser Arg Ala Ser Phe Pro Gly Pro Ser Glu

1 5 10 15

Leu His Ser Glu Asp Ser Arg Phe Arg Glu Leu Arg Lys Arg Tyr Glu

Page 5

A-1850-WO-PCT_SL.txt

20 25 30 Asp Leu Leu Thr Arg Leu Arg Ala Asn Gln Ser Trp Glu Asp Ser Asn 35 40 45 Thr Asp Leu Val Pro Ala Pro Ala Val Arg Ile Leu Thr Pro Glu Val 50 55 60 Arg Leu Gly Ser Gly Gly His Leu His Leu Arg Ile Ser Arg Ala Ala 65 70 75 80 Leu Pro Glu Gly Leu Pro Glu Ala Ser Arg Leu His Arg Ala Leu Phe 85 90 95 Arg Leu Ser Pro Thr Ala Ser Arg Ser Trp Asp Val Thr Arg Pro Leu 100 105 110 Arg Arg Gln Leu Ser Leu Ala Arg Pro Gln Ala Pro Ala Leu His Leu 115 120 125 Arg Leu Ser Pro Pro Pro Ser Gln Ser Asp Gln Leu Leu Ala Glu Ser 130 135 140 Ser Ser Ala Arg Pro Gln Leu Glu Leu His Leu Arg Pro Gln Ala Ala 145 150 155 160 Arg Gly Arg Arg Arg Ala Arg Ala Arg Asn Gly Asp His Cys Pro Leu 165 170 175 Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu 180 185 190 Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val 195 200 205 Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met 210 215 220 His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val 225 230 235 240 Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile 245 250 255 Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu 260 265 270 Ala Lys Asp Cys His Cys Ile 275

<210> 9

Page 6

A-1850-WO-PCT_SL.txt <211> 816 <212> DNA <213> Mus sp.

<400> 9 tcgcaggggg acgccctggc aatgcctgaa cagcgaccct ccggccctga gtcccaactc 60 aacgccgacg agctacgggg tcgcttccag gacctgctga gccggctgca tgccaaccag 120 agccgagagg actcgaactc agaaccaagt cctgacccag ctgtccggat actcagtcca 180 gaggtgagat tggggtccca cggccagctg ctactccgcg tcaaccgggc gtcgctgagt 240 cagggtctcc ccgaagccta ccgcgtgcac cgagcgctgc tcctgctgac gccgacggcc 300 cgcccctggg acatcactag gcccctgaag cgtgcgctca gcctccgggg accccgtgct 360 cccgcattac gcctgcgcct gacgccgcct ccggacctgg ctatgctgcc ctctggcggc 420 acgcagctgg aactgcgctt acgggtagcc gccggcaggg ggcgccgaag cgcgcatgcg 480 cacccaagag actcgtgccc actgggtccg gggcgctgct gtcacttgga gactgtgcag 540 gcaactcttg aagacttggg ctggagcgac tgggtgctgt ccccgcgcca gctgcagctg 600 agcatgtgcg tgggcgagtg tccccacctg tatcgctccg cgaacacgca tgcgcagatc 660 aaagcacgcc tgcatggcct gcagcctgac aaggtgcctg ccccgtgctg tgtcccctcc 720 agctacaccc cggtggttct tatgcacagg acagacagtg gtgtgtcact gcagacttat 780 gatgacctgg tggcccgggg ctgccactgc gcttga 816 <210> 10 <211> 271 <212> PRT <213> Mus sp. <400> 10

Ser 1 Gln Gly Asp Ala Leu 5 Ala Met Pro Glu Gln Arg 10 Pro Ser Gly 15 Pro Glu Ser Gln Leu Asn Ala Asp Glu Leu Arg Gly Arg Phe Gln Asp Leu 20 25 30 Leu Ser Arg Leu His Ala Asn Gln Ser Arg Glu Asp Ser Asn Ser Glu 35 40 45 Pro Ser Pro Asp Pro Ala Val Arg Ile Leu Ser Pro Glu Val Arg Leu 50 55 60 Gly Ser His Gly Gln Leu Leu Leu Arg Val Asn Arg Ala Ser Leu Ser 65 70 75 80 Gln Gly Leu Pro Glu Ala Tyr Arg Val His Arg Ala Leu Leu Leu Leu 85 90 95 Thr Pro Thr Ala Arg Pro Trp Asp Ile Thr Arg Pro Leu Lys Arg Ala 100 105 110

Page 7

A-1850-WO-PCT_SL.txt

Leu Ser Leu 115 Arg Gly Pro Arg Ala Pro Ala 120 Leu Arg Leu 125 Arg Leu Thr Pro Pro Pro Asp Leu Ala Met Leu Pro Ser Gly Gly Thr Gln Leu Glu 130 135 140 Leu Arg Leu Arg Val Ala Ala Gly Arg Gly Arg Arg Ser Ala His Ala 145 150 155 160 His Pro Arg Asp Ser Cys Pro Leu Gly Pro Gly Arg Cys Cys His Leu 165 170 175 Glu Thr Val Gln Ala Thr Leu Glu Asp Leu Gly Trp Ser Asp Trp Val 180 185 190 Leu Ser Pro Arg Gln Leu Gln Leu Ser Met Cys Val Gly Glu Cys Pro 195 200 205 His Leu Tyr Arg Ser Ala Asn Thr His Ala Gln Ile Lys Ala Arg Leu 210 215 220 His Gly Leu Gln Pro Asp Lys Val Pro Ala Pro Cys Cys Val Pro Ser 225 230 235 240 Ser Tyr Thr Pro Val Val Leu Met His Arg Thr Asp Ser Gly Val Ser 245 250 255 Leu Gln Thr Tyr Asp Asp Leu Val Ala Arg Gly Cys His Cys Ala

260 265 270 <210> 11 <211> 339 <212> DNA <213> Homo sapiens <400> 11 gcgcgcaacg gggaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc 60 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 120 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag 180 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 240 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 300 tatgatgact tgttagccaa agactgccac tgcatatga 339 <210> 12 <211> 112 <212> PRT <213> Homo sapiens <400> 12

Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg 1 5 10 15

Page 8

A-1850-WO-PCT_SL.txt

Leu His Thr Val 20 Arg Ala Ser Leu Glu Asp 25 Leu Gly Trp Ala 30 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys 35 40 45 Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser 50 55 60 Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro 65 70 75 80 Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 85 90 95 Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 100 105 110

<210> 13 <211> 351 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 13 atgagcgcgc atgcgcaccc aagagactcg tgcccactgg gtccggggcg ctgctgtcac 60 ctggagactg tgcaggcaac tcttgaagac ttgggctgga gcgactgggt gttgtccccg 120 cgccagctgc agctgagcat gtgcgtgggc gagtgtcccc acctgtatcg ctccgcgaac 180 acgcatgcgc agatcaaagc acgcctgcat ggcctgcagc ctgacaaggt gcctgccccg 240 tgctgtgtcc cctccagcta caccccggtg gttcttatgc acaggacaga cagtggtgtg 300 tcactgcaga cttatgatga cctggtggcc cggggctgcc actgcgcttg a 351 <210> 14 <211> 116 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 14

Met Ser Ala His Ala His Pro Arg Asp Ser Cys Pro Leu Gly Pro Gly 1 5 10 15

Arg Cys Cys His Leu Glu Thr Val Gln Ala Thr Leu Glu Asp Leu Gly 20 25 30

Page 9

A-1850-WO-PCT_SL.txt

Trp Ser Asp 35 Trp Val Leu Ser Pro 40 Arg Gln Leu Gln Leu 45 Ser Met Cys Val Gly Glu Cys Pro His Leu Tyr Arg Ser Ala Asn Thr His Ala Gln 50 55 60 Ile Lys Ala Arg Leu His Gly Leu Gln Pro Asp Lys Val Pro Ala Pro 65 70 75 80 Cys Cys Val Pro Ser Ser Tyr Thr Pro Val Val Leu Met His Arg Thr 85 90 95 Asp Ser Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Val Ala Arg Gly 100 105 110 Cys His Cys Ala

115 <210> 15 <211> 12 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 15

Glu Arg Lys Ser Ser Val Glu Cys Pro Pro Cys Pro

1 5 10 <210> 16 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 16

Ala Pro 1 Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Page 10

A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Ala Leu Pro Ala 100 Pro Ile Glu Lys Pro Arg Glu 115 Pro Gln Val Tyr Thr 120 Thr Lys 130 Asn Gln Val Ser Leu 135 Trp Ser 145 Asp Ile Ala Val Glu 150 Trp Glu Tyr Lys Thr Thr Pro 165 Pro Val Leu Tyr Ser Lys Leu 180 Thr Val Asp Lys Phe Ser Cys 195 Ser Val Met His Glu 200 Lys Ser Leu Ser Leu Ser Pro Gly

210 215

Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Leu Pro Pro Ser Arg 125 Asp Glu Leu Cys Leu Val Lys 140 Gly Phe Tyr Pro Ser Asn Gly 155 Gln Pro Glu Asn Asn 160 Asp Ser 170 Asp Gly Ser Phe Phe 175 Leu Ser 185 Arg Trp Gln Gln Gly 190 Asn Val Ala Leu His Asn His 205 Tyr Thr Gln

<210> 17 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 17

Ala Pro Glu 1 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80

Page 11

A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn Gly Lys Glu Tyr 85 Lys Cys 90 Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 115 120 125 Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 18 <211> 20 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 18

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

Gly Gly Gly Ser 20 <210> 19 <211> 1047 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 19 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc Page 12

A-1850-WO-PCT_SL.txt

ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgtggtg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg catatga 1047

<210> 20 <211> 348 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 20 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Page 13

A-1850-WO-PCT_SL.txt

85 90 95

Ala Leu Pro Ala Pro Ile Glu 100 Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 115 120 125 Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly 225 230 235 240 Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 245 250 255 Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro 260 265 270 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 275 280 285 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 290 295 300 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 305 310 315 320 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 325 330 335 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 340 345

<210> 21

Page 14

A-1850-WO-PCT_SL.txt <211> 654 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 21 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgagctg cgcggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcgt cagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 654 <210> 22 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 22 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95

Page 15

A-1850-WO-PCT_SL.txt

Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 23 <211> 1046 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 23 cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc 60 tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc 120 ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc aagacaaagc 180 cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc 240 aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc ctcccagccc 300 ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag gtgaccaccc 360 tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc ctggtcaaag 420 gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg gagaacaact 480 acgacaccac gcctcccgtg ctggactccg acggctcctt cttcctctat agcgacctca 540 ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg 600 ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtgga ggtggtggat 660 ccggaggcgg tggaagcgga ggtggtggat ctggaggcgg tggaagcgcg cgcaacggag 720 accactgtcc gctcgggccc gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg 780

Page 16

A-1850-WO-PCT_SL.txt

aagacctggg ctgggccgat tgggtgctgt cgccacggga ggtgcaagtg accatgtgca 840 tcggcgcgtg cccgagccag ttccgggcgg caaacatgca cgcgcagatc aagacgagcc 900 tgcaccgcct gaagcccgac acggtgccag cgccctgctg cgtgcccgcc agctacaatc 960 ccatggtgct cattcaaaag accgacaccg gggtgtcgct ccagacctat gatgacttgt 1020 tagccaaaga ctgccactgc atatga 1046

<210> 24 <211> 348 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 24 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Page 17

A-1850-WO-PCT_SL.txt

180 185 190

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly 225 230 235 240 Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 245 250 255 Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro 260 265 270 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 275 280 285 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 290 295 300 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 305 310 315 320 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 325 330 335 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

340 345 <210> 25 <211> 112 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 25

Ala Arg Asn Gly Asp Asp Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg 1 5 10 15 Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp 20 25 30 Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys 35 40 45 Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser

50 55 60

Page 18

A-1850-WO-PCT_SL.txt

Leu His 65 Arg Leu Lys Pro 70 Asp Thr Val Pro Ala Pro Cys 75 Cys Val Pro 80 Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 85 90 95 Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

100 105 110 <210> 26 <211> 1047 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 26

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gacgactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg catatga 1047

<210> 27 <211> 348 <212> PRT <213> Artificial Sequence <220>

Page 19

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 27 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly 225 230 235 240 Asp Asp Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 245 250 255

Page 20

A-1850-WO-PCT_SL.txt

Arg Ala Ser Leu 260 Glu Asp Leu Gly Trp 265 Ala Asp Trp Val Leu 270 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 275 280 285 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 290 295 300 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 305 310 315 320 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 325 330 335 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

340 345 <210> 28 <211> 230 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Description of polypeptide <400> 28 Gly Gly Gly Glu Arg Lys Ser 1 5 Artificial Sequence: Synthetic Ala Ser Val Glu Cys 10 Pro Pro Cys Pro 15 Pro Pro Val Ala Gly Pro Ser 20 Val Phe 25 Leu Phe Pro Pro Lys 30 Pro Lys Asp Thr Leu Met Ile Ser Arg 35 Thr Pro 40 Glu Val Thr Cys Val 45 Val Val Asp Val Ser His Glu Asp Pro 50 55 Glu Val Gln Phe Asn 60 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 65 70 Lys Thr Lys Pro 75 Arg Glu Glu Gln Phe 80 Asn Ser Thr Phe Arg Val Val 85 Ser Val Leu Thr 90 Val Val His Gln 95 Asp Trp Leu Asn Gly Lys Glu Tyr 100 Lys Cys 105 Lys Val Ser Asn Lys 110 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg

115 120 125

Page 21

A-1850-WO-PCT_SL.txt

Glu Pro Gln 130 Val Tyr Thr Leu 135 Pro Pro Ser Arg Glu 140 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly

225 230 <210> 29 <211> 227 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Description of Artificial Sequence Synthetic polypeptide <400> 29 Val Glu Cys Pro Pro 10 Cys Pro Ala Pro Pro 15 Val Glu Arg Lys 1 Ser Ser 5 Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 20 25 30 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 35 40 45 His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 50 55 60 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 65 70 75 80 Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn 85 90 95 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro 100 105 110 Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Page 22

A-1850-WO-PCT_SL.txt

115 120 125 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 130 135 140 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 145 150 155 160 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 165 170 175 Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 180 185 190 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 195 200 205 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 210 215 220 Ser Pro Gly

225 <210> 30 <211> 21 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 30

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15

Gly Gly Gly Gly Ser 20 <210> 31 <211> 1833 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 31 ggaggtggag agcgcaaatc ttctgtcgag tgcccaccgt gcccagcacc acctgtggca 60 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca cgtgcgtggt ggtggacgtg agccacgaag accccgaggt ccagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa aaccacggga ggagcagttc Page 23 240

A-1850-WO-PCT_SL.txt

aacagcacgt tccgtgtggt cagcgtcctc accgttgtgc accaggactg gctgaacggc 300 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccag cccccatcga gaaaaccatc 360 tccaaaacca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 480 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacacctccc 540 atgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt ggaggtggcg gtagcggtgg cggaggttca 720 ggtggcggcg gaagcggtgg aggaggttca gagcggaaat ccagcgttga atgtcctccg 780 tgccctgctc cacccgtcgc ggggcctagt gtcttccttt tccctccaaa accaaaggat 840 acactgatga tcagccggac ccccgaggtt acgtgcgtcg tcgtcgatgt ctcccacgag 900 gatccagagg tccaattcaa ctggtacgtg gacggggtcg aggtgcataa tgcaaagaca 960 aagccacggg aagagcagtt taactctact ttccgcgtgg tttctgtgct gaccgtggtg 1020 caccaagatt ggctcaacgg caaggagtac aagtgcaagg taagcaataa ggggctccct 1080 gcccccattg agaagactat ctccaagaca aagggacagc cacgcgagcc acaagtctat 1140 acactccccc cttcccgcga agaaatgacc aagaatcagg ttagcctgac atgcttggtt 1200 aagggtttct acccctctga catagccgtg gagtgggaga gcaatggaca accagagaac 1260 aactacaaga ccaccccacc catgctggat agcgacggtt cattctttct gtatagtaag 1320 cttaccgtgg acaagtcccg gtggcaacaa ggaaatgtct tttcatgctc tgtgatgcac 1380 gaggccttgc ataatcacta tactcagaag agcttgagcc tcagccccgg atctggaggt 1440 ggcggatccg ggggcggtgg aagcggaggt ggtggatcgg gaggcggtgg aagcgcgcgc 1500 aacggcgacc actgtccgct cgggcccgga cgttgctgcc gtctgcacac ggtccgcgcg 1560 tcgctggaag acctgggctg ggccgattgg gtgctgtcgc cacgggaggt gcaagtgacc 1620 atgtgcatcg gcgcgtgccc gagccagttc cgggcggcaa acatgcacgc gcagatcaag 1680 acgagcctgc accgcctgaa gcccgacacg gtgccagcgc cctgctgcgt gcccgccagc 1740 tacaatccca tggtgctcat tcaaaagacc gacaccgggg tgtcgctcca gacctatgat 1800 gacttgttag ccaaagactg ccactgcata tga 1833

<210> 32 <211> 610 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 32

Gly Gly Gly Glu Arg Lys Ser Ser Val Glu Cys Pro Pro Cys Pro Ala Page 24

1 5 A-1850-WO- 10 -PCT_SL.txt 15 Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 65 70 75 80 Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Gly Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Arg Lys Ser Ser Val 245 250 255 Glu cys Pro Pro cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 260 265 270 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Page 25

A-1850-WO-PCT_SL.txt

275 280 285 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 290 295 300 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 305 310 315 320 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val 325 330 335 Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 355 360 365 Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 370 375 380 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 405 410 415 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 420 425 430 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 435 440 445 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 450 455 460 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ser Gly Gly 465 470 475 480 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 485 490 495 Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 500 505 510 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 515 520 525 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 530 535 540 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Pag e 26

A-1850-WO-PCT_SL.txt

545 550 555 560 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 565 570 575 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 580 585 590 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

595 600 605

Cys Ile 610 <210> 33 <211> 218 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 33 Pro 5 Pro Val Ala Gly Pro 10 Ser Val Phe Leu Phe 15 Pro Gly Gly 1 Gly Ala Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 20 25 30 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn 35 40 45 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 50 55 60 Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 65 70 75 80 Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 85 90 95 Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 100 105 110 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 115 120 125 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 130 135 140 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 145 150 155 160

Page 27

A-1850-WO-PCT_SL.txt

Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 165 170 175 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 180 185 190 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 195 200 205 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 34 <211> 25 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 34

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 35 <211> 215 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 35

Ala 1 Pro Pro Val Ala 5 Gly Pro Ser Val Phe 10 Leu Phe Pro Pro Lys 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 20 25 30 Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 35 40 45 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 50 55 60 Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 65 70 75 80

Page 28

A-1850-WO-PCT_SL.txt

Asp Trp Leu Asn Gly Lys Glu 85 Tyr Lys Cys 90 Lys Val Ser Asn Lys 95 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro 100 105 110 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 115 120 125 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 130 135 140 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 145 150 155 160 Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 165 170 175 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 180 185 190 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 195 200 205 Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 36 <211> 1809 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 36 ggcggtggag ctccgccggt ggctggaccc tcagtgttcc tctttccacc gaagccgaag 60 gacaccctta tgattagccg gaccccagag gtcacttgcg tcgtcgtgga cgtgtcccat 120 gaggatcccg aagtgcagtt taactggtat gtggacggag tggaggtcca taacgccaag 180 accaagccaa gggaagaaca gttcaatagc accttccggg tggtgtccgt gctcaccgtg 240 gtgcatcaag actggctgaa tggcaaagag tacaaatgta aggtgtcaaa caaggggctc 300 ccagccccta ttgaaaagac catctcaaag actaagggac agccacgcga acctcaagtg 360 tataccctcc cgccttcacg cgaagaaatg actaagaatc aggtcagcct tacttgtctg 420 gtcaagggct tctacccgag cgacattgca gtcgaatggg agagcaatgg tcagccagag 480 aataactaca agaccactcc tcccatgctt gatagcgatg gaagcttttt cctttacagc 540 aagcttactg tggataagtc tcgctggcaa cagggaaatg tgttcagctg ttcagtgatg 600 catgaagcac tccacaatca ttacacccag aagtcactca Page 29 gcctctcacc cggaggagga 660

A-1850-WO-PCT_SL.txt

ggcggttctg gtggaggagg gtctggaggt ggagggagcg gcggaggcgg gtctggcggt 720 ggtgggtctg agaggaagtc atcagtggaa tgcccaccat gccctgctcc tcccgtggcc 780 ggtccgagcg tgtttctctt cccacctaag cccaaggaca ctctgatgat ctcacggact 840 ccggaagtga cttgtgtggt ggtggacgtg tctcatgagg accctgaagt gcagttcaac 900 tggtacgtgg acggcgtgga ggtgcacaat gctaagacca agcctagaga ggaacagttc 960 aattccacct ttcgcgtggt gagcgtcctg accgtcgtgc accaggactg gcttaacgga 1020 aaggaataca agtgcaaggt gtccaacaaa ggccttccag ctcccattga gaaaaccatc 1080 tctaaaacta agggtcaacc aagggaaccc caagtctaca ccctccctcc gtctagagaa 1140 gagatgacca aaaaccaggt gtccctgacc tgtctggtga agggatttta cccctcagac 1200 atcgccgtgg agtgggaaag caacggacag cccgaaaaca actataagac tacccctcct 1260 atgctggact cagacggatc tttcttcctc tatagcaagc tcactgtgga caaatccaga 1320 tggcaacaag ggaatgtgtt ctcatgcagc gtgatgcacg aggctcttca caaccactat 1380 acccagaaga gcctgtctct ttcacctggt tccggaggtg gtgggagcgg agggggtgga 1440 tcaggtggtg gagggtccgg aggcggagga tccgcacgga atggcgacca ctgtccactg 1500 ggacccggaa gatgttgtcg cctccacacc gtgagggcct ctctggagga ccttggctgg 1560 gccgactggg tcctgtcacc tcgggaggtc caagtcacca tgtgtatcgg agcctgcccc 1620 agccaattca gagcagcaaa tatgcacgca cagattaaga ccagcctgca tcggcttaaa 1680 cctgatactg tgccggctcc ttgttgcgtg ccagcatctt acaacccgat ggtgctgatc 1740 cagaaaaccg ataccggtgt ctccctccag acttacgacg acctccttgc aaaggactgc 1800

cattgcatc 1809 <210> 37 <211> 591 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 37 Pro 10 Ser Val Phe Leu Phe 15 Pro Gly 1 Gly Gly Ala Pro 5 Pro Val Ala Gly Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 20 25 30 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn 35 40 45 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 50 55 60

Page 30

A-1850-WO-PCT_SL.txt

Glu Glu 65 Gln Phe Asn Ser Thr 70 Phe Arg Val Val 75 Ser Val Leu Thr Val 80 Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 85 90 95 Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 100 105 110 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 115 120 125 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 130 135 140 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 145 150 155 160 Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 165 170 175 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 180 185 190 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 195 200 205 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly 210 215 220 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 225 230 235 240 Gly Gly Ser Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 245 250 255 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 260 265 270 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn 275 280 285 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 290 295 300 Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 305 310 315 320 Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 325 330 335

Page 31

A-1850-WO-PCT_SL.txt

Asn Lys Gly Leu 340 Pro Ala Pro Ile Glu 345 Lys Thr Ile Ser Lys 350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 355 360 365 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 370 375 380 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 385 390 395 400 Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 405 410 415 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 420 425 430 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 435 440 445 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala 465 470 475 480 Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu 485 490 495 His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val 500 505 510 Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro 515 520 525 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu 530 535 540 His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala 545 550 555 560 Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser 565 570 575 Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 580 585 590

<210> 38 <211> 216 <212> PRT

Page 32

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 38 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 39 <211> 217 <212> PRT <213> Artificial Sequence

Page 33

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 39 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 40 <211> 23 <212> PRT <213> Artificial Sequence

Page 34

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 40

Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Val Ala Ser Ser Gly 1 5 10 15

Ser Gly Ser Ala Thr His Leu 20 <210> 41 <211> 1053 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 41

gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccga gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tgggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggaca agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt cacctggcgg atccggttct 660 gctactggtg gttccggctc cgtcgcaagc tctggttcag gcagtgcgac tcatctggca 720 cggaacgggg accattgtcc cctgggacct ggtcggtgct gccggcttca caccgtcaga 780 gcctctctgg aggaccttgg atgggctgat tgggtgctga gccctcggga ggtgcaagtc 840 accatgtgca tcggggcctg ccctagccag ttccgcgcag ccaacatgca cgctcagatc 900 aaaacctctc ttcacagact gaagcccgac accgtgccag caccttgctg tgtgccggcc 960 tcttataacc ccatggtcct cattcagaaa accgacaccg gagtgtcact tcagacttac 1020 gatgacctcc tggccaagga ctgccactgc ata 1053

<210> 42 <211> 351 <212> PRT <213> Artificial Sequence <220>

Page 35

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 42 Ala Pro Glu 1 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Ser Gly Ser Ala Thr Gly Gly 210 215 220 Ser Gly Ser Val Ala Ser Ser Gly Ser Gly Ser Ala Thr His Leu Ala 225 230 235 240 Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu 245 250 255

Page 36

A-1850-WO-PCT_SL.txt

His Thr Val Arg 260 Ala Ser Leu Glu Asp 265 Leu Gly Trp Ala Asp 270 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro 275 280 285 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu 290 295 300 His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala 305 310 315 320 Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser 325 330 335 Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 340 345 350

<210> 43 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 43 gcgccggaac tgctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 ctgccgccga gccgcgaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tatgatacca ccccgccggt gctggatagc gatggcagct tttttctgta tagcgatctg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcaa a 651 <210> 44 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

Page 37

A-1850-WO-PCT_SL.txt

<400> 44 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 45 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

Page 38

A-1850-WO-PCT_SL.txt <400> 45

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 46 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 46 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Page 39

A-1850-WO-PCT_SL.txt

85 90 95

Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 47 <211> 217 <212> PRT <213> Artificial Sequence

Page 40

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 47 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 48 <211> 216 <212> PRT <213> Artificial Sequence <220>

Page 41

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 48 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<220>

<221> source <210> 49 <211> 984 <212> DNA <213> Artificial Sequence

Page 42

A-1850-WO-PCT_SL.txt <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 49 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 50 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 50

Ala Pro 1 Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Page 43

A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

<210> 51 <211> 654

Page 44

325

A-1850-WO-PCT_SL.txt <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 51

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 654 <210> 52 <211> 112 <212> PRT <213> Artificial Sequence <220> <221> source <223> /note =Description of Artificial Sequence: Synthetic polypeptide <400> 52 Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg 1 5 10 15 Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp 20 25 30 Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys 35 40 45 Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser 50 55 60 Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro 65 70 75 80 Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 85 90 95 Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

Page 45

A-1850-WO-PCT_SL.txt

100 105 110 <210> 53 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 53 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 54 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 54

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30

Page 46

Val Val Asp 35 Val Ser His Glu A-1850-WO-PCT_SL.txt Asn Trp Tyr Asp 40 Pro Glu Val Lys Phe 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His cys Pro 210 215 220 Leu Gly Pro Gly Arg cys cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met cys Ile Gly Ala cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro cys cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300

Page 47

A-1850-WO-PCT_SL.txt

Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320

Leu Ala Lys Asp Cys His Cys Ile 325 <210> 55 <211> 109 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 55 Leu Gly Pro Gly Arg Cys Cys Arg 10 Leu His 15 Thr Gly Asp 1 His Cys Pro 5 Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser 20 25 30 Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 35 40 45 Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg 50 55 60 Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr 65 70 75 80 Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln 85 90 95 Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 100 105

<210> 56 <211> 975 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 56 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300

Page 48

A-1850-WO-PCT_SL.txt cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 57 <211> 325 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 57 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125

Page 49

Thr Lys 130 Asn Gln Val Ser Leu 135 A-1850-WO-PCT_SL.txt Phe Tyr Pro Thr Cys Leu Val Lys Gly 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 245 250 255 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320 Asp Cys His Cys Ile

325 <210> 58 <211> 4 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 58

Gly Gly Gly Gly <210> 59

Page 50

A-1850-WO-PCT_SL.txt <211> 996 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 59 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 gcgcgcgacg gagaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

<210> 60 <211> 332 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 60

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

35 40 45

Page 51

Val Asp 50 Gly Val Glu Val His 55 A-1850-WO-PCT_SL.txt Arg Glu Glu Asn Ala Lys Thr Lys 60 Pro Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Arg Asp Gly 210 215 220 Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 225 230 235 240 Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro 245 250 255 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 260 265 270 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 275 280 285 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 290 295 300 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 305 310 315 320

Page 52

A-1850-WO-PCT_SL.txt

Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330 <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 61

Gly Gly Gly Gly Ser

1 5 <210> 62 <211> 1002 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 62 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccgcgcgca acggagacca ctgtccgctc gggcccgggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctgggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcatat ga 1002

<210> 63 <211> 333 <212> PRT

Page 53

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 63 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Ala Arg Asn 210 215 220 Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr 225 230 235 240

Page 54

A-1850-WO-PCT_SL.txt

Val Arg Ala Ser Leu 245 Glu Asp Leu Gly Trp Ala 250 Asp Trp Val Leu 255 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 260 265 270 Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg 275 280 285 Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr 290 295 300 Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln 305 310 315 320 Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330

<210> 64 <211> 10 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 64

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 <210> 65 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 65 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540

Page 55

accgtggaca agagcaggtg A- gcagcagggg 1850-WO-PCT aacgtcttct SL.txt catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgc gcgcaacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 66 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 66 Phe Leu Phe Pro Pro 15 Lys Ala Pro 1 Glu Leu Leu Gly 5 Gly Pro Ser Val 10 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160

Page 56

Tyr Asp Thr Thr Pro 165 Pro Val A-1850-WO-PCT_SL.txt Leu Asp Ser Asp Gly Ser 170 Phe Phe 175 Leu Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 67 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 67 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct Page 57 ccaacaaagc cctcccagcc 300

A-1850-WO-PCT_SL.txt

cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 68 <211> 338 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Descriptior polypeptide of Gly Artificial Sequence Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 68 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Asn 65 Ser Thr Tyr 70 Arg Val Val Ser Val 75 Leu Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly 85 Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr Ile 105 Ser Lys Ala Lys Gly 110 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met

115 120 125

Page 58

A-1850-WO-PCT_SL.txt

Thr Lys Asn Gln Val 130 Ser Leu Thr 135 Cys Leu Val Lys 140 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 69 <211> 5 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 69

Page 59

A-1850-WO-PCT_SL.txt

Gly Gly Gly Gly Pro 1 5 <210> 70 <211> 999 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 70

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cccgcgcgca acggagacca ctgtccgctc gggcccgggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctgggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcata 999

<210> 71 <211> 333 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 71 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr cys Val 20 25 30

Page 60

A-1850-WO-PCT_SL.txt

Val Val Asp Val 35 Ser His Glu Asp 40 Pro Glu Val Lys Phe 45 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Pro Ala Arg Asn 210 215 220 Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr 225 230 235 240 Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser 245 250 255 Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 260 265 270 Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg 275 280 285 Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr

290 295 300

Page 61

A-1850-WO-PCT_SL.txt

Asn 305 Pro Met Val Leu Ile Gln 310 Lys Thr Asp Thr 315 Gly Val Ser Leu Gln 320 Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330

<210> 72 <211> 10 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 72

Gly Gly Gly Gly Pro Gly Gly Gly Gly Pro

1 5 10 <210> 73 <211> 1017 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 73 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cctggaggcg gtggaccagc gcgcaacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga 1017

Page 62

A-1850-WO-PCT_SL.txt <210> 74 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 74 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Pro Gly Gly Gly 210 215 220

Page 63

A-1850-WO-PCT_SL.txt

Gly 225 Pro Ala Arg Asn Gly 230 Asp His Cys Pro Leu 235 Gly Pro Gly Arg Cys 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 75 <211> 5 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 75

Gly Gly Gly Gly Gln

1 5 <210> 76 <211> 1002 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 76 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct Page 64 ccaacaaagc cctcccagcc 300

A-1850-WO-PCT_SL.txt

cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 actgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 caggcgcgca acggagacca ctgtccgctc gggcccgggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctgggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcatat ga 1002

<210> 77 <211> 333 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Description polypeptide of Gly Artificial Sequence Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 77 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Asn 65 Ser Thr Tyr 70 Arg Val Val Ser Val 75 Leu Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly 85 Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr Ile 105 Ser Lys Ala Lys Gly 110 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met

115 120 125

Page 65

A-1850-WO-PCT_SL.txt

Thr Lys Asn Gln Val 130 Ser Leu Thr 135 Cys Leu Val Lys 140 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Ala Arg Asn 210 215 220 Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr 225 230 235 240 Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser 245 250 255 Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 260 265 270 Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg 275 280 285 Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr 290 295 300 Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln 305 310 315 320 Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330

<210> 78 <211> 10 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 78

Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln

1 5 10

Page 66

A-1850-WO-PCT_SL.txt <210> 79 <211> 1017 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 79

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cagggaggcg gtggacaggc gcgcaacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga 1017

<210> 80 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 80

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

35 40 45

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A-1850-WO-PCT_SL.txt

Val Asp Gly 50 Val Glu Val His Asn 55 Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly 210 215 220 Gly Gln Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr

305 310 315 320

Page 68

A-1850-WO-PCT_SL.txt

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 81 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 81

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cagggaggcg gtggacaggc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 82 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 82

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15

Page 69

A-1850-WO-PCT_SL.txt

Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr 30 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly 210 215 220 Gly Gln Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285

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A-1850-WO-PCT_SL.txt

Thr Ser Leu His Arg Leu Lys 295 Pro Asp Thr Val Pro Ala 300 Pro Cys Cys 290 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 83 <211> 1005 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 83

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cagggaggcg gtggacaggg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 720 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 780 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccgggc ggcaaacatg 840 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 900 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 960 ctccagacct atgatgactt gttagccaaa gactgccact gcata 1005

<210> 84 <211> 335 <212> PRT <213> Artificial Sequence

Page 71

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 84 Ala Pro Glu 1 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly 210 215 220 Gly Gln Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu 225 230 235 240 His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Page 72

245 A-1850-WO- 250 -PcT_SL.txt 255 Leu Ser Pro Arg Glu Val Gln Val Thr Met cys Ile Gly Ala cys Pro 260 265 270 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu 275 280 285 His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro cys cys Val Pro Ala 290 295 300 Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser 305 310 315 320 Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp cys His cys Ile 325 330 335

<210> 85 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 85 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

Page 73

A-1850-WO-PCT_SL.txt

Ser Asp 145 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 160 150 155 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 86 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 86 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

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A-1850-WO-PCT_SL.txt

Ser Asp 145 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 160 150 155 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 87 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 87 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tgggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggaca agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt cacctggcgc gcgcgacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 88

Page 75

A-1850-WO-PCT_SL.txt <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 88 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240

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A-1850-WO-PCT_SL.txt

Glu Asp Leu Gly Trp Ala Asp Trp 245 Val Leu Ser 250 Pro Arg Glu Val 255 Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 89 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 89 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651 <210> 90 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

Page 77

A-1850-WO-PCT_SL.txt polypeptide <400> 90

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215 <210> 91 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

Page 78

A-1850-WO-PCT_SL.txt

<400> 91 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 92 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

Page 79

A-1850-WO-PCT_SL.txt <400> 92

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 93 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 93 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Page 80

A-1850-WO-PCT_SL.txt

85 90 95

Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

<210> 94 <211> 651 <212> DNA <213> Artificial Sequence

325

Page 81

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 94 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tgggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggaca agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a 651 <210> 95 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 95 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840

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A-1850-WO-PCT_SL.txt ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata

900

960

984 <210> 96 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 96 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

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A-1850-WO-PCT_SL.txt

Lys Ser 210 Leu Ser Leu Ser Pro 215 Gly Ala Arg Asp Gly Asp 220 His cys Pro Leu Gly Pro Gly Arg cys cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met cys Ile Gly Ala cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro cys cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp cys His cys Ile

325 <210> 97 <211> 975 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 97 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720

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A-1850-WO-PCT_SL.txt

ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 98 <211> 325 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 98 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Page 85

180 A-1850-WO- 185 -PCT_SL.txt 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 245 250 255 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320 Asp Cys His Cys Ile

325 <210> 99 <211> 996 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 99 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540

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accgtggaca agagcaggtg A- gcagcagggg 1850-WO-PCT aacgtcttct SL.txt catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg tggaggtggt 660 gcgcgcgacg gagaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

<210> 100 <211> 332 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 100 Phe Leu Phe Pro Pro 15 Lys Ala Pro 1 Glu Leu Leu Gly 5 Gly Pro Ser Val 10 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160

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Tyr Asp Thr Thr Pro 165 Pro Val A-1850-WO-PCT_SL.txt Leu Asp Ser Asp Gly Ser 170 Phe Phe 175 Leu Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Arg Asp Gly 210 215 220 Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 225 230 235 240 Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro 245 250 255 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 260 265 270 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 275 280 285 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 290 295 300 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 305 310 315 320 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330

<210> 101 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 101 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca Page 88 gcctgacctg cctggtcaaa 420

A-1850-WO-PCT_SL.txt

ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 102 <211> 338 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Description polypeptide of Gly Artificial Sequence Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 102 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Asn 65 Ser Thr Tyr 70 Arg Val Val Ser Val 75 Leu Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly 85 Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr Ile 105 Ser Lys Ala Lys Gly 110 Gln Pro Arg Glu 115 Pro Gln Val Cys Thr Leu Pro 120 Pro Ser Arg 125 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135 140

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A-1850-WO-PCT_SL.txt

Ser Asp 145 Ile Ala Val Glu Trp 150 Glu Ser Asn Gly Gln 155 Pro Glu Asn Asn 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 103 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 103 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac

120

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cctgaggtca agttcaactg A- gtacgtggac 1850-WO-PCT ggcgtggagg SL.txt tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 cagggaggcg gtggacaggc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 104 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 104 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110

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A-1850-WO-PCT_SL.txt

Pro Arg Glu 115 Pro Gln Val Cys Thr 120 Leu Pro Pro Ser Arg 125 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly 210 215 220 Gly Gln Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile <210> 105 <211> 217 <212> PRT <213> Artificial Sequence <220>

Page 92

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 105 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 106 <211> 216 <212> PRT <213> Artificial Sequence <220> <221> source

Page 93

A-1850-WO-PCT_SL.txt <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 106 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 107 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

Page 94

A-1850-WO-PCT_SL.txt polynucleotide <400> 107 gcgccggaac tgctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 tgcccgccga gccgcgaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tatgatacca ccccgccggt gctggatagc gatggcagct tttttctgta tagcgatctg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcgg cggcggcggc 660 agcggcggcg gcggcagcgc gcgcaacggc gatcattgcc cgctgggccc gggccgctgc 720 tgccgcctgc ataccgtgcg cgcgagcctg gaagatctgg gctgggcgga ttgggtgctg 780 agcccgcgcg aagtgcaggt gaccatgtgc attggcgcgt gcccgagcca gtttcgcgcg 840 gcgaacatgc atgcgcagat taaaaccagc ctgcatcgcc tgaaaccgga taccgtgccg 900 gcgccgtgct gcgtgccggc gagctataac ccgatggtgc tgattcagaa aaccgatacc 960 ggcgtgagcc tgcagaccta tgatgatctg ctggcgaaag attgccattg catt 1014 <210> 108 <211> 338 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 108

Ala Pro Glu 1 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80

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A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 325 330 335

Cys Ile

Page 96

A-1850-WO-PCT_SL.txt <210> 109 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 109 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tgtcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651

<210> 110 <211> 585 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 110

Asp 1 Ala His Lys Ser Glu 5 Val Ala His Arg Phe 10 Lys Asp Leu Gly 15 Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro

85 90 95

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A-1850-WO-PcT_SL.txt

Glu Arg Asn Glu 100 cys Phe Leu Gln His 105 Lys Asp Asp Asn Pro 110 Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu cys cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu cys cys His Gly Asp Leu Leu Glu cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu cys cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350 Tyr Glu Thr Thr Leu Glu Lys cys cys Ala Ala Ala Asp Pro His Glu 355 360 365

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A-1850-WO-PCT_SL.txt

Cys Tyr 370 Ala Lys Val Phe Asp Glu 375 Phe Lys Pro Leu 380 Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu 580 585

<210> 111 <211> 2154 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

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A-1850-WO-PCT_SL.txt

<400> 111 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggagg tggtggatcc ggaggcggtg gaagcggagg tggtggatct 1800 ggaggcggtg gaagcgcgcg caacggagac cactgtccgc tcgggcccgg gcgttgctgc 1860 cgtctgcaca cggtccgcgc gtcgctggaa gacctgggct gggccgattg ggtgctgtcg 1920 ccacgggagg tgcaagtgac catgtgcatc ggcgcgtgcc cgagccagtt ccgggcggca 1980 aacatgcacg cgcagatcaa gacgagcctg caccgcctga agcccgacac ggtgccagcg 2040

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A-1850-WO-PCT_SL.txt ccctgctgcg tgcccgccag ctacaatccc atggtgctca ttcaaaagac cgacaccggg gtgtcgctcc agacctatga tgacttgtta gccaaagact gccactgcat atga

2100

2154 <210> 112 <211> 717 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 112 Lys Asp Leu Gly Glu 15 Asp 1 Ala His Lys Ser 5 Glu Val Ala His Arg 10 Phe Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205

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A-1850-WO-PCT_SL.txt

Arg Ala Phe Lys Ala Trp Ala 215 Val Ala Arg Leu Ser 220 Gln Arg Phe Pro 210 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350 Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu 355 360 365 Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480

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A-1850-WO-PCT_SL.txt

Leu Val Asn Arg Arg 485 Pro Cys Phe Ser Ala Leu Glu 490 Val Asp Glu 495 Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly 580 585 590 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn 595 600 605 Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr 610 615 620 Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser 625 630 635 640 Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 645 650 655 Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg 660 665 670 Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr 675 680 685 Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln 690 695 700 Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 705 710 715

<210> 113 <211> 9 <212> PRT <213> Artificial Sequence <220>

<221> source

Page 103

A-1850-WO-PCT_SL.txt <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 113

Gly Ser Pro Ala Pro Ala Pro Gly Ser

1 5 <210> 114 <211> 2121 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 114 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500

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A-1850-WO-PCT_SL.txt

gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cccagctcca gctccaggaa gcgcgcgcaa cggagaccac 1800 tgtccgctcg ggcccgggcg ttgctgccgt ctgcacacgg tccgcgcgtc gctggaagac 1860 ctgggctggg ccgattgggt gctgtcgcca cgggaggtgc aagtgaccat gtgcatcggc 1920 gcgtgcccga gccagttccg ggcggcaaac atgcacgcgc agatcaagac gagcctgcac 1980 cgcctgaagc ccgacacggt gccagcgccc tgctgcgtgc ccgccagcta caatcccatg 2040 gtgctcattc aaaagaccga caccggggtg tcgctccaga cctatgatga cttgttagcc 2100 aaagactgcc actgcatatg a 2121

<210> 115 <211> 706 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Description of Artificial Sequence Synthetic polypeptide Val <400> 115 Lys Ser 5 Glu Asp Leu Gly 15 Glu Asp Ala 1 His Ala His Arg 10 Phe Lys Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

Page 105

130 135 A-1850-WO- -PCT_SL.txt 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350 Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu 355 360 365 Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Page 106

A-1850-WO-PCT_SL.txt

405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Ser Pro Ala Pro Ala Pro 580 585 590 Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 595 600 605 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 610 615 620 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 625 630 635 640 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 645 650 655 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 660 665 670 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Page 10 7

A-1850-WO-PCT_SL.txt 675 680 685

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 690 695 700

Cys Ile 705 <210> 116 <211> 14 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 116

Gly Ser Pro Ala Pro Ala Pro Pro Ala Pro Ala Pro Gly Ser 1 5 10 <210> 117 <211> 2136 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 117 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960

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A-1850-WO-PCT_SL.txt

gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cccagctcca gctccacccg cacctgcccc tggaagcgcg 1800 cgcaacggag accactgtcc gctcgggccc gggcgttgct gccgtctgca cacggtccgc 1860 gcgtcgctgg aagacctggg ctgggccgat tgggtgctgt cgccacggga ggtgcaagtg 1920 accatgtgca tcggcgcgtg cccgagccag ttccgggcgg caaacatgca cgcgcagatc 1980 aagacgagcc tgcaccgcct gaagcccgac acggtgccag cgccctgctg cgtgcccgcc 2040 agctacaatc ccatggtgct cattcaaaag accgacaccg gggtgtcgct ccagacctat 2100 gatgacttgt tagccaaaga ctgccactgc atatga 2136

<210> 118 <211> 711 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 118

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu 1 5 10 15 Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys

50 55 60

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Ser 65 Leu His Thr Leu Phe 70 Gly Asp Lys Leu Cys Thr 75 Val Ala Thr Leu 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335

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Arg His Pro Asp Tyr Ser Val 340 Val Leu 345 Leu Leu Arg Leu Ala 350 Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu 355 360 365 Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Ser Pro Ala Pro Ala Pro 580 585 590 Pro Ala Pro Ala Pro Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu 595 600 605

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Gly Pro Gly Arg Cys Cys Arg 615 Leu His Thr Val Arg Ala 620 Ser Leu Glu 610 Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val 625 630 635 640 Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met 645 650 655 His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val 660 665 670 Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile 675 680 685 Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu 690 695 700 Ala Lys Asp Cys His Cys Ile

705 710 <210> 119 <211> 11 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 119

Gly Ser Ala Ala Gln Ala Ala Gln Gln Gly Ser

1 5 10 <210> 120 <211> 2127 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 120 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420

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gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cgccgctcag gctgcacagc aaggaagcgc gcgcaacgga 1800 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 1860 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 1920 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 1980 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 2040 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 2100 ttagccaaag actgccactg catatga 2127

<210> 121 <211> 708 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

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A-1850-WO-PCT_SL.txt polypeptide <400> 121

Asp 1 Ala His Lys Ser 5 Glu Val Ala His Arg Phe 10 Lys Asp Leu Gly 15 Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Page 114

260 A-1850-WO 265 -PcT_SL.txt 270 Ser Lys Leu Lys Glu cys cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350 Tyr Glu Thr Thr Leu Glu Lys cys cys Ala Ala Ala Asp Pro His Glu 355 360 365 cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys cys cys Lys His Pro Glu Ala Lys Arg Met Pro cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys cys cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Page 115

A-1850-WO-PCT_SL.txt

530 535 540

Lys 545 Ala Val Met Asp Asp 550 Phe Ala Ala Phe Val 555 Glu Lys Cys Cys Lys 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Ser Ala Ala Gln Ala Ala 580 585 590 Gln Gln Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly 595 600 605 Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly 610 615 620 Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys 625 630 635 640 Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln 645 650 655 Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro 660 665 670 Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr 675 680 685 Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp 690 695 700

Cys His Cys Ile 705 <210> 122 <211> 18 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 122

Gly Ser Ala Ala Gln Ala Ala Gln Gln Ala Ala Gln Ala Ala Gln Gln 1 5 10 15

Gly Ser <210> 123 <211> 2148

Page 116

A-1850-WO-PCT_SL.txt <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 123 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cgccgctcag gctgcacagc aagcagccca agcagctcag 1800

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cagggaagcg cgcgcaacgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 1860 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 1920 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccgggc ggcaaacatg 1980 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 2040 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 2100 ctccagacct atgatgactt gttagccaaa gactgccact gcatatga 2148

<210> 124 <211> 715 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 124

Asp Ala 1 His Lys Ser Glu Val 5 Ala His Arg Phe 10 Lys Asp Leu Gly 15 Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170 175

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A-1850-WO-PCT_SL.txt

Cys Leu Leu Pro 180 Lys Leu Asp Glu Leu 185 Arg Asp Glu Gly Lys 190 Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350 Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu 355 360 365 Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445

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Ala Glu Asp 450 Tyr Leu Ser Val 455 Val Leu Asn Gln Leu 460 Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Ser Ala Ala Gln Ala Ala 580 585 590 Gln Gln Ala Ala Gln Ala Ala Gln Gln Gly Ser Ala Arg Asn Gly Asp 595 600 605 His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg 610 615 620 Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg 625 630 635 640 Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg 645 650 655 Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys 660 665 670 Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro 675 680 685 Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr 690 695 700 Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 705 710 715

Page 120

A-1850-WO-PCT_SL.txt <210> 125 <211> 22 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic peptide <400> 125

Gly Gly Asn Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala 1 5 10 15

Ala Ala Lys Ala Gly Gly 20 <210> 126 <211> 2175 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 126 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140

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gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggagg caacgccgag gctgccgcta aggaagccgc tgccaaggag 1800 gccgcagcaa aagaggctgc agctaaggcc ggaggagcgc gcaacggaga ccactgtccg 1860 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctgggc 1920 tgggccgatt gggtgctgtc gccacgggag gtgcaagtga ccatgtgcat cggcgcgtgc 1980 ccgagccagt tccgggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 2040 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 2100 attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 2160 tgccactgca tatga 2175

<210> 127 <211> 724 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Description of Artificial Sequence Synthetic polypeptide Val <400> 127 Lys Ser Glu 5 Asp 1 Ala His Ala His Arg 10 Phe Lys Asp Leu Gly 15 Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 55 60 Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu 65 70 75 80

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Arg Glu Thr Tyr Gly 85 Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg 325 330 335 Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr 340 345 350

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Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu 355 360 365 Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro 370 375 380 Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu 385 390 395 400 Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro 405 410 415 Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys 420 425 430 Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys 435 440 445 Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His 450 455 460 Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser 465 470 475 480 Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr 485 490 495 Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp 500 505 510 Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala 515 520 525 Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu 530 535 540 Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys 545 550 555 560 Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val 565 570 575 Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Asn Ala Glu Ala Ala 580 585 590 Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala 595 600 605 Lys Ala Gly Gly Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly 610 615 620

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Arg 625 Cys Cys Arg Leu His 630 Thr Val Arg Ala Ser 635 Leu Glu Asp Leu Gly 640 Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys 645 650 655 Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln 660 665 670 Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro 675 680 685 Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr 690 695 700 Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp 705 710 715 720

Cys His Cys Ile <210> 128 <211> 30 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 128

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 30 <210> 129 <211> 2184 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 129 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa

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120

180

240

300

A-1850-WO-PCT_SL.txt

tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggagg tggtggctct ggaggcggtg gaagcggagg cggtggatcc 1800 ggaggcggtg gaagcggagg tggtggatct ggaggcggtg gaagcgcgcg caacggagac 1860 cactgtccgc tcgggcccgg gcgttgctgc cgtctgcaca cggtccgcgc gtcgctggaa 1920 gacctgggct gggccgattg ggtgctgtcg ccacgggagg tgcaagtgac catgtgcatc 1980 ggcgcgtgcc cgagccagtt ccgggcggca aacatgcacg cgcagatcaa gacgagcctg 2040 caccgcctga agcccgacac ggtgccagcg ccctgctgcg tgcccgccag ctacaatccc 2100 atggtgctca ttcaaaagac cgacaccggg gtgtcgctcc agacctatga tgacttgtta 2160 gccaaagact gccactgcat atga 2184

<210> 130 <211> 777

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A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 130

Asp 1 Ala His Lys Ser 5 Glu Val Ala His Arg 10 Phe Lys Asp Leu Gly 15 Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu 50 55 60 Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr 65 70 75 80 Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val 85 90 95 Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys 100 105 110 Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala 115 120 125 Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln 130 135 140 Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro 145 150 155 160 Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala 165 170 175 Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile 180 185 190 Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala 195 200 205 Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys 210 215 220 Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys 225 230 235 240

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A-1850-WO-PCT_SL.txt

Ala Ser Ser Ala Gly Glu Arg Ala 260 Phe Pro Lys 275 Ala Thr Lys 290 Val His Asp 305 Asp Arg Ala Ile Ser Ser Lys Ser His Cys Ile 340 Pro Ser Leu 355 Ala Tyr Ala 370 Glu Ala Ala 385 Arg Arg His Lys Thr Tyr Glu His Glu Cys Tyr 420 Glu Pro Gln 435 Asn Gly Glu 450 Tyr Lys Val 465 Pro Gln Val Gly Lys Val Gly Pro Cys Ala Glu 500

Lys 245 Gln Arg Leu Phe Lys Ala Trp Glu Phe Ala Glu 280 Thr Glu Cys 295 Cys Asp Leu 310 Ala Lys Leu 325 Lys Glu Cys Ala Glu Val Glu Ala Asp Phe Val 360 Lys Asp Val 375 Phe Pro Asp 390 Tyr Ser Thr 405 Thr Leu Glu Ala Lys Val Phe Leu Ile Lys Gln 440 Phe Gln Asn 455 Ala Ser Thr 470 Pro Thr Ser 485 Lys Cys Cys Asp Tyr Leu Ser

Lys Cys 250 Ala Ser Ala 265 Val Ala Arg Val Ser Lys Leu His Gly Asp Leu 300 Tyr Ile Cys 315 Glu Cys Glu 330 Lys Pro Asn 345 Asp Glu Met Glu Ser Lys Asp Leu Gly Met Phe 380 Val Val Leu 395 Leu Lys Cys 410 Cys Ala Asp 425 Glu Phe Lys Asn Cys Glu Leu Leu Leu Val Arg 460 Leu Val Glu 475 Val Lys His 490 Pro Glu Val 505 Val Leu Asn

Leu Gln Lys 255 Phe Leu Ser 270 Gln Arg Val 285 Thr Asp Leu Leu Glu Cys Ala Asn Gln Asp Ser 320 Leu Leu Glu 335 Lys Pro Ala 350 Asp Leu Val 365 Cys Lys Asn Leu Tyr Glu Tyr Leu Arg Leu Ala 400 Ala Ala Asp 415 Pro Pro Leu 430 Val Glu Phe 445 Glu Gln Leu Tyr Thr Lys Lys Ser Arg Asn Leu 480 Ala Lys Arg 495 Met Gln Leu 510 Cys Val

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A-1850-WO-PCT_SL.txt

Leu His Glu 515 Lys Thr Pro Val Ser 520 Asp Arg Val Thr Lys 525 Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp 530 535 540 Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His 545 550 555 560 Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln 565 570 575 Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu 580 585 590 Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys 595 600 605 Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys 610 615 620 Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser 625 630 635 640 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 645 650 655 Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly Asp His Cys 660 665 670 Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser 675 680 685 Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val 690 695 700 Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala 705 710 715 720 Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp 725 730 735 Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val 740 745 750 Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp 755 760 765 Leu Leu Ala Lys Asp Cys His Cys Ile 770 775

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A-1850-WO-PCT_SL.txt <210> 131 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 131 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

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A-1850-WO-PCT_SL.txt <210> 132 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 132 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 133

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A-1850-WO-PCT_SL.txt <211> 975 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 133 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 134 <211> 325 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 134

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

35 40 45

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Val Asp 50 Gly Val Glu Val His 55 A-1850-WO-PCT_SL.txt Arg Glu Glu Asn Ala Lys Thr Lys 60 Pro Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 245 250 255 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320

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A-1850-WO-PCT_SL.txt

Asp Cys His Cys Ile 325 <210> 135 <211> 654 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 135 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 654 <210> 136 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 136 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600

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A-1850-WO-PCT_SL.txt gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata

660

720

780

840

900

960

984 <210> 137 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 137 Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Page 135

A-1850-WO-PCT_SL.txt

165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 138 <211> 996 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 138 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420

Page 136

A-1850-WO-PCT_SL.txt ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 gcgcgcgacg gagaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

<210> 139 <211> 332 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 139 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

Page 137

Ser 145 Asp Ile Ala Val Glu 150 Trp A Glu Tyr Asp Thr Thr Pro 165 Pro Val Leu Tyr Ser Asp Leu 180 Thr Val Asp Lys Phe Ser Cys 195 Ser Val Met His Glu 200 Lys Ser 210 Leu Ser Leu Ser Pro 215 Gly Asp 225 His Cys Pro Leu Gly 230 Pro Gly Arg Ala Ser Leu Glu 245 Asp Leu Gly Arg Glu Val Gln 260 Val Thr Met Cys Arg Ala Ala 275 Asn Met His Ala Gln 280 Lys Pro 290 Asp Thr Val Pro Ala 295 Pro Pro 305 Met Val Leu Ile Gln 310 Lys Thr Tyr Asp Asp Leu Leu 325 Ala Lys Asp

1850-WO-PCT_SL.txt

Ser Asn Gly 155 Gln Pro Glu Asn Asn 160 Asp Ser 170 Asp Gly Ser Phe Phe 175 Leu Ser 185 Arg Trp Gln Gln Gly 190 Asn Val Ala Leu His Asn His 205 Tyr Thr Gln Gly Gly Gly Gly 220 Ala Arg Asp Gly Arg Cys Cys 235 Arg Leu His Thr Val 240 Trp Ala 250 Asp Trp Val Leu Ser 255 Pro Ile 265 Gly Ala Cys Pro Ser 270 Gln Phe Ile Lys Thr Ser Leu 285 His Arg Leu Cys Cys Val Pro 300 Ala Ser Tyr Asn Asp Thr Gly 315 Val Ser Leu Gln Thr 320 Cys His 330 Cys Ile

<210> 140 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 140

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

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A-1850-WO-PCT_SL.txt 40 45

Val Asp 50 Gly Val Glu Val His Asn Ala Lys 55 Thr Lys 60 Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 141 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 141

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

35 40 45

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Val Asp 50 Gly Val Glu Val His Asn Ala Lys 55 Thr Lys 60 Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 142 <211> 975 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 142 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360

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ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 143 <211> 325 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Descriptior polypeptide of Gly Artificial Sequence Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 143 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Gly 65 Ser Thr Tyr 70 Arg Val Val Ser Val 75 Leu Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly 85 Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr Ile 105 Ser Lys Ala Lys Gly 110 Gln Pro Arg Glu 115 Pro Gln Val Cys Thr Leu Pro 120 Pro Ser Arg 125 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

Page 141

130 135 A-1850-WO- -PCT_SL.txt 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 245 250 255 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320 Asp Cys His Cys Ile

325

120

180 <210> 144 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 144 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa

Page 142

A-1850-WO-PCT_SL.txt ccccgcgaag aacagtacgg gagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tgggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggaca agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a 651 <210> 145 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 145 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984 <210> 146 <211> 328 <212> PRT <213> Artificial Sequence

Page 143

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 146

Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255

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Val Thr Met Cys 260 Ile Gly Ala Cys Pro Ser 265 Gln Phe Arg Ala 270 Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 147 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 147 Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

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A-1850-WO-PCT_SL.txt

Ser Asp 145 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 160 150 155 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215 <210> 148 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Description polypeptide of Gly Artificial Sequence Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 148 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Ala Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Gly 65 Ser Thr Tyr 70 Arg Val Val Ser Val 75 Leu Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly 85 Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr Ile 105 Ser Lys Ala Lys Gly 110 Gln Pro Arg Glu 115 Pro Gln Val Tyr Thr Cys Pro 120 Pro Ser Arg 125 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135 140

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A-1850-WO-PCT_SL.txt

Ser Asp 145 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 160 150 155 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 149 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 149 gcgccggaac tgctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtatgg cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 tgcccgccga gccgcaaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tataaaacca ccccgccggt gctgaaaagc gatggcagct tttttctgta tagcaaactg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcgc gcgcaacggc 660 gatcattgcc cgctgggccc gggccgctgc tgccgcctgc ataccgtgcg cgcgagcctg 720 gaagatctgg gctgggcgga ttgggtgctg agcccgcgcg aagtgcaggt gaccatgtgc 780 attggcgcgt gcccgagcca gtttcgcgcg gcgaacatgc atgcgcagat taaaaccagc 840 ctgcatcgcc tgaaaccgga taccgtgccg gcgccgtgct gcgtgccggc gagctataac 900 ccgatggtgc tgattcagaa aaccgatacc ggcgtgagcc tgcagaccta tgatgatctg 960 ctggcgaaag attgccattg catt 984 <210> 150 <211> 328

Page 147

A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 150 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240

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Glu Asp Leu Gly Trp Ala Asp Trp 245 Val Leu Ser 250 Pro Arg Glu Val 255 Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 151 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 151 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tgtcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651 <210> 152 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

Page 149

A-1850-WO-PCT_SL.txt

<400> 152 gcgccggaac tgctgggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtatgg cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 tgcccgccga gccgcaaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tataaaacca ccccgccggt gctgaaaagc gatggcagct tttttctgta tagcaaactg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcgc gcgcgatggc 660 gatcattgcc cgctgggccc gggccgctgc tgccgcctgc ataccgtgcg cgcgagcctg 720 gaagatctgg gctgggcgga ttgggtgctg agcccgcgcg aagtgcaggt gaccatgtgc 780 attggcgcgt gcccgagcca gtttcgcgcg gcgaacatgc atgcgcagat taaaaccagc 840 ctgcatcgcc tgaaaccgga taccgtgccg gcgccgtgct gcgtgccggc gagctataac 900 ccgatggtgc tgattcagaa aaccgatacc ggcgtgagcc tgcagaccta tgatgatctg 960 ctggcgaaag attgccattg catt 984

<210> 153 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 153 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala Pro 1 Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80

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A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile 325

<210> 154 <211> 210 <212> PRT <213> Artificial Sequence

Page 151

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 154 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 155 <211> 209 <212> PRT <213> Artificial Sequence

Page 152

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 155 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 156 <211> 954 <212> DNA <213> Artificial Sequence <220>

Page 153

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 156

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 157 <211> 318 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 157

Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80

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A-1850-WO-PCT_SL.txt

Glu Tyr Lys Cys Lys 85 Val Ser Asn Lys Ala Leu 90 Pro Ala Pro Ile 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220 Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu 225 230 235 240 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser 245 250 255 Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 158 <211> 633 <212> DNA <213> Artificial Sequence <220>

<221> source

Page 155

A-1850-WO-PCT_SL.txt <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 158 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtaaa tga 633

<210> 159 <211> 963 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 159 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900

Page 156

960

A-1850-WO-PCT_SL.txt accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc ata

963 <210> 160 <211> 321 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 160 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Page 157

A-1850-WO-PCT_SL.txt

Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly 220 Arg Cys Cys 210 215 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 225 230 235 240 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 245 250 255 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile <210> 161 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Description polypeptide of Pro Artificial Sequence Synthetic <400> 161 Phe Leu 5 Phe Pro Ser 1 Val Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Page 158

A-1850-WO-PCT_SL.txt

100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 162 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 162 Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110

Page 159

A-1850-WO-PCT_SL.txt

Thr Leu Pro 115 Pro Ser Arg Glu Glu Met Thr 120 Lys Asn Gln 125 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 163 <211> 954 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 163 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840

Page 160

A-1850-WO-PCT_SL.txt gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata

900

954 <210> 164 <211> 318 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 164 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Page 161

A-1850-WO-PCT_SL.txt

Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220 Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu 225 230 235 240 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser 245 250 255 Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 165 <211> 630 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 165 ccatccgtgt tcctgtttcc tccaaagccg aaggacaccc tgatgatctc aagaactccg 60 gaagtgactt gcgtcgtcgt ggacgtgtca catgaggatc cagaggtcaa gttcaattgg 120 tatgtggacg gagtggaagt gcataacgcc aagaccaaac cccgcgaaga acagtacaat 180 agcacctacc gcgtggtgag cgtccttact gtgctccacc aggactggct taatgggaag 240 gaatacaagt gtaaggtgtc caacaaggcc ctccccgctc ccatcgaaaa gaccatctca 300 aaggcaaagg ggcaaccaag ggaacctcaa gtgtacaccc tgcctccgtg caggaaggag 360 atgaccaaga accaggtcag cctgacttgt ctcgtgaagg gcttctatcc cagcgatatt 420 gctgtggaat gggagtcaaa tggccagccc gagaataact acaaaactac cccacccgtg 480 ctgaaatctg atgggtcctt cttcctttac tccaagctga ccgtggacaa gagccgctgg 540 caacaaggca atgtctttag ctgctcagtg atgcatgagg ctctccataa tcactacact 600 cagaagtcac tgtccctgtc tccgggtaaa 630 <210> 166 <211> 963 <212> DNA <213> Artificial Sequence

Page 162

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 166

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960

ata 963 <210> 167 <211> 321 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 167

Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Ser Arg Thr Pro 20 Glu Val Thr Cys Val 25 Val Val Asp Val Ser 30 His Glu Asp Pro Glu 35 Val Lys Phe Asn Trp 40 Tyr Val Asp Gly Val 45 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

50 55 60

Page 163

Val 65 Val Ser Val Leu Thr 70 Val A-1850-WO-PCT_SL.txt Asn Gly Lys 80 Leu His Gln Asp Trp 75 Leu Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys 210 215 220 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 225 230 235 240 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 245 250 255 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile

Page 164

A-1850-WO-PCT_SL.txt <210> 168 <211> 227 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 168

Asp 1 Lys Thr His Thr 5 Cys Pro Pro Cys Pro 10 Ala Pro Glu Leu Leu 15 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220

Pro Gly Lys

Page 165

A-1850-WO-PCT_SL.txt

225 <210> 169 <211> 226 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 169 Leu Leu 15 Gly Asp 1 Lys Thr His Thr Cys 5 Pro Pro Cys Pro Ala 10 Pro Glu Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220

Page 166

A-1850-WO-PCT_SL.txt

Pro Gly 225 <210> 170 <211> 1005 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 170

gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tgggagagca atgggcagcc ggagaacaac tacgacacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta tagcgacctc accgtggaca agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 720 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 780 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccgggc ggcaaacatg 840 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 900 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 960 ctccagacct atgatgactt gttagccaaa gactgccact gcata 1005

<210> 171 <211> 335 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 171

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

1 5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Page 167

20 A-1850-WO 25 -PCT_SL.txt 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu 225 230 235 240 His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val 245 250 255 Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro 260 265 270 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu 275 280 285 His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Page 168

A-1850-WO-PCT_SL.txt

290 295 300

Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser 305 310 315 320 Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

325 330 335 <210> 172 <211> 681 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 172 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccggaagga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctgaagtcc 540 gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtaa a 681 <210> 173 <211> 1014 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 173 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300

Page 169

tgcaaggtct ccaacaaagc A- cctcccagcc 1850-WO-PCT. cccatcgaga SL.txt aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tgggagagca atgggcagcc ggagaacaac tacgacacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta tagcgacctc accgtggaca agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtgc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 174 <211> 338 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Descriptior polypeptide of Pro Artificial Sequence Synthetic Gly Pro Cys Pro Ala Pro 10 Glu Leu Leu 15 <400> 174 Asp Lys Thr 1 His Thr Cys 5 Gly Pro Ser Val 20 Phe Leu Phe Pro Pro 25 Lys Pro Lys Asp Thr 30 Leu Met Ile Ser Arg 35 Thr Pro Glu Val Thr Cys 40 Val Val Val Asp 45 Val Ser His Glu Asp Pro 50 Glu Val Lys Phe 55 Asn Trp Tyr Val Asp 60 Gly Val Glu Val His Asn Ala 65 Lys Thr Lys 70 Pro Arg Glu Glu Gln Tyr 75 Gly Ser Thr Tyr 80 Arg Val Val Ser Val Leu 85 Thr Val Leu His Gln Asp 90 Trp Leu Asn 95 Gly Lys Glu Tyr Lys 100 Cys Lys Val Ser Asn 105 Lys Ala Leu Pro Ala 110 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120 125

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A-1850-WO-PCT_SL.txt

Tyr Thr 130 Leu Pro Pro Ser Arg Glu 135 Glu Met Thr Lys 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 225 230 235 240 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 245 250 255 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 260 265 270 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 275 280 285 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 290 295 300 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 305 310 315 320 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

325 330 335

Cys Ile <210> 175 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 175

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

Page 171

1 5 A-1850-WO 10 -PCT_SL.txt 15 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 176 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 176

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

1 5 10 15

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A-1850-WO-PCT_SL.txt

Ser Arg Thr Pro Glu 20 Val Thr Cys Val 25 Val Val Asp Val Ser 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 177 <211> 954 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 177 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg

Page 173

120

A-1850-WO-PCT_SL.txt

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 178 <211> 318 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 178 Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110

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A-1850-WO-PCT_SL.txt

Thr Leu Pro 115 Pro Ser Arg Glu Glu 120 Met Thr Lys Asn Gln 125 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220 Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu 225 230 235 240 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser 245 250 255 Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 179 <211> 633 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 179 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg

120

Page 175

A-1850-WO-PCT_SL.txt tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtaaa tga 633 <210> 180 <211> 963 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 180 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960 ata 963 <210> 181 <211> 321 <212> PRT

Page 176

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 181 Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys 210 215 220 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 225 230 235 240

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A-1850-WO-PCT_SL.txt

Trp Val Leu Ser Pro 245 Arg Glu Val Gln Val 250 Thr Met Cys Ile Gly 255 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile <210> 182 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Descriptior polypeptide of Pro Artificial Sequence: Synthetic Pro Lys Pro 10 Lys Asp <400> 182 Phe Pro Ser 1 Val Phe Leu 5 Thr Leu Met 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Page 178

A -1850-WO· -PCT _SL. txt 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 183 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 183 Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140

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A-1850-WO-PCT_SL.txt

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 184 <211> 954 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 184

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 185 <211> 318

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A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 185 Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220 Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu 225 230 235 240

Page 181

A-1850-WO-PCT_SL.txt

Ser Pro Arg Glu Val 245 Gln Val Thr Met Cys 250 Ile Gly Ala Cys Pro 255 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 186 <211> 630 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 186 ccatccgtgt tcctgtttcc tccaaagccg aaggacaccc tgatgatctc aagaactccg 60 gaagtgactt gcgtcgtcgt ggacgtgtca catgaggatc cagaggtcaa gttcaattgg 120 tatgtggacg gagtggaagt gcataacgcc aagaccaaac cccgcgaaga acagtacggg 180 agcacctacc gcgtggtgag cgtccttact gtgctccacc aggactggct taatgggaag 240 gaatacaagt gtaaggtgtc caacaaggcc ctccccgctc ccatcgaaaa gaccatctca 300 aaggcaaagg ggcaaccaag ggaacctcaa gtgtacaccc tgcctccgtg caggaaggag 360 atgaccaaga accaggtcag cctgacttgt ctcgtgaagg gcttctatcc cagcgatatt 420 gctgtggaat gggagtcaaa tggccagccc gagaataact acaaaactac cccacccgtg 480 ctgaaatctg atgggtcctt cttcctttac tccaagctga ccgtggacaa gagccgctgg 540 caacaaggca atgtctttag ctgctcagtg atgcatgagg ctctccataa tcactacact 600 cagaagtcac tgtccctgtc tccgggtaaa 630 <210> 187 <211> 963 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 187 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60

Page 182

gaggtcacat gcgtggtggt A- ggacgtgagc 1850-WO-PCT cacgaagacc SL.txt ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960

ata 963 <210> 188 <211> 321 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note=Description of Pro Artificial Sequence Synthetic Ile polypeptide Phe Pro Lys Pro Lys Asp 10 Thr Leu Met 15 <400> 188 Pro Ser Val 1 Phe Leu 5 Ser Arg Thr Pro 20 Glu Val Thr Cys Val 25 Val Val Asp Val Ser His 30 Glu Asp Pro Glu 35 Val Lys Phe Asn Trp Tyr 40 Val Asp Gly Val 45 Glu Val His Asn Ala Lys 50 Thr Lys Pro Arg 55 Glu Glu Gln Tyr Gly 60 Ser Thr Tyr Arg Val Val Ser 65 Val Leu Thr 70 Val Leu His Gln Asp Trp 75 Leu Asn Gly Lys 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

85 90 95

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Lys Thr Ile Ser 100 Lys Ala Lys Gly Gln 105 Pro Arg Glu Pro Gln 110 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys 210 215 220 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 225 230 235 240 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 245 250 255 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile <210> 189 <211> 113 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

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A-1850-WO-PCT_SL.txt polypeptide <400> 189

Met 1 Ala Arg Asn Gly Asp His 5 Cys Pro Leu Gly Pro Gly Arg Cys Cys 10 15 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 20 25 30 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 35 40 45 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 50 55 60 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 65 70 75 80 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 85 90 95 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys

100 105 110

Ile <210> 190 <211> 342 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 190 atggcgcgca acggggacca ctgtccgctc gggcccgggc gttgctgccg tctgcacacg 60 gtccgcgcgt cgctggaaga cctgggctgg gccgattggg tgctgtcgcc acgggaggtg 120 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 180 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 240 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 300 acctatgatg acttgttagc caaagactgc cactgcatat aa 342 <210> 191 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

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<400> 191 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 192 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

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A-1850-WO-PCT_SL.txt

<400> 192 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 193 <211> 954 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 193

Page 187

ccgtcagtct tcctcttccc A- cccaaaaccc 1850-WO-PCT aaggacaccc _SL.txt tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 194 <211> 318 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 194 Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95

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Lys Thr Ile Ser 100 Lys Ala Lys A-1850-WO-PCT_SL.txt Gln 110 Val Tyr Gly Gln 105 Pro Arg Glu Pro Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220 Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu 225 230 235 240 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser 245 250 255 Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 195 <211> 630 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 195 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct

Page 189

A-1850-WO-PCT_SL.txt gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtaaa 630 <210> 196 <211> 963 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 196 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960 ata 963

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A-1850-WO-PCT_SL.txt <210> 197 <211> 321 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 197 Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys 210 215 220 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Page 191

A-1850-WO-PCT_SL.txt

225 230 235 240 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 245 250 255 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile <210> 198 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 198 Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125

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A-1850-WO-PCT_SL.txt

Thr Cys 130 Leu Val Lys Gly Phe 135 Tyr Pro Ser Asp Ile 140 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys 210 <210> 199 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 199 Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125

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A-1850-WO-PCT_SL.txt

Thr Cys 130 Leu Val Lys Gly Phe 135 Tyr Pro Ser Asp Ile 140 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly <210> 200 <211> 954 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 200 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgga gaccactgtc cgctcgggcc cgggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

Page 194

A-1850-WO-PCT_SL.txt <210> 201 <211> 318 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 201 Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His 210 215 220

Page 195

Thr 225 Val Arg Ala Ser Leu 230 Glu A-1850-WO-PCT_SL.txt Trp Val Leu 240 Asp Leu Gly Trp Ala Asp 235 Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser 245 250 255 Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His 260 265 270 Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser 275 280 285 Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu 290 295 300 Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315

<210> 202 <211> 630 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 202

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatg ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtaaa 630

<210> 203 <211> 963 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

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A-1850-WO-PCT_SL.txt

<400> 203 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960

ata 963 <210> 204 <211> 321 <212> PRT <213> Artificial Sequence

<220> <221> source <223> /note^Description of Pro Artificial Sequence Synthetic Ile polypeptide Phe Pro Lys Pro Lys Asp 10 Thr Leu Met 15 <400> 204 Pro Ser Val 1 Phe Leu 5 Ser Arg Thr Pro 20 Glu Val Thr Cys Val 25 Val Val Asp Val Ser His 30 Glu Asp Pro Glu 35 Val Lys Phe Asn Trp Tyr 40 Val Asp Gly Val 45 Glu Val His Asn Cys Lys 50 Thr Lys Pro Arg 55 Glu Glu Gln Tyr Gly 60 Ser Thr Tyr Arg Val Val Ser 65 Val Cys Thr 70 Val Leu His Gln Asp Trp 75 Leu Asn Gly Lys 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

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85 A-1850-WO 90 -PCT_SL.txt 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205 Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys 210 215 220 Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 225 230 235 240 Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 245 250 255 Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 260 265 270 Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 275 280 285 Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 290 295 300 Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys 305 310 315 320

Ile <210> 205 <211> 212 <212> PRT <213> Artificial Sequence

Page 198

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 205

Gly 1 Gly Pro Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 145 150 155 160 Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

Ser Pro Gly Lys 210 <210> 206 <211> 211 <212> PRT <213> Artificial Sequence <220>

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A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 206 Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Gly 1 Gly Pro Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

Ser Pro Gly 210

<210> 207 <211> 960 <212> DNA <213> Artificial Sequence <220> <221> source

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A-1850-WO-PCT_SL.txt <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 207 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtggagacc actgtccgct cgggcccggg 660 cgttgctgcc gtctgcacac ggtccgcgcg tcgctggaag acctgggctg ggccgattgg 720 gtgctgtcgc cacgggaggt gcaagtgacc atgtgcatcg gcgcgtgccc gagccagttc 780 cgggcggcaa acatgcacgc gcagatcaag acgagcctgc accgcctgaa gcccgacacg 840 gtgccagcgc cctgctgcgt gcccgccagc tacaatccca tggtgctcat tcaaaagacc 900 gacaccgggg tgtcgctcca gacctatgat gacttgttag ccaaagactg ccactgcata 960

<210> 208 <211> 320 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 208 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Le u 1 5 10 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Se r 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Gl u 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Th r 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu As n 65 70 75 80

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A-1850-WO-PCT_SL.txt

Gly Lys Glu Tyr Lys 85 Cys Lys Val Ser Asn 90 Lys Ala Leu Pro Ala 95 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205 Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg 210 215 220 Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp 225 230 235 240 Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys 245 250 255 Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser 260 265 270 Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro 275 280 285 Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 290 295 300 Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315 320

<210> 209 <211> 636 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

Page 202

A-1850-WO-PCT_SL.txt polynucleotide

<400> 209 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 360 aaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 480 cccgtgctga agtccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtaaa 636

<210> 210 <211> 969 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 210 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtgcgcgcg acggagacca ctgtccgctc 660 gggcccgggc gttgctgccg tctgcacacg gtccgcgcgt cgctggaaga cctgggctgg 720 gccgattggg tgctgtcgcc acgggaggtg caagtgacca tgtgcatcgg cgcgtgcccg 780 agccagttcc gggcggcaaa catgcacgcg cagatcaaga cgagcctgca ccgcctgaag 840 cccgacacgg tgccagcgcc ctgctgcgtg cccgccagct acaatcccat ggtgctcatt 900 caaaagaccg acaccggggt gtcgctccag acctatgatg acttgttagc caaagactgc 960

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A-1850-WO-PCT_SL.txt cactgcata

969 <210> 211 <211> 323 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 211 Gly 1 Gly Pro Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205 Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Page 204

210 215 A-1850-WO -PCT_SL.txt 220 Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp 225 230 235 240 Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile 245 250 255 Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile 260 265 270 Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys 275 280 285 Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp 290 295 300 Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys 305 310 315 320

His Cys Ile <210> 212 <211> 212 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 212 Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Gly 1 Gly Pro Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110

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A-1850-WO-PCT_SL.txt

Val Tyr Thr 115 Leu Pro Pro Cys Arg 120 Lys Glu Met Thr Lys 125 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 145 150 155 160 Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

Ser Pro Gly Lys 210 <210> 213 <211> 211 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 213 Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Gly 1 Gly Pro Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110

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A-1850-WO-PCT_SL.txt

Val Cys Thr 115 Leu Pro Pro Ser Arg Glu Glu Met Thr 120 Lys 125 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

Ser Pro Gly 210 <210> 214 <211> 960 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 214 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt gcaccctgcc cccatcccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtggagacc actgtccgct cgggcccggg 660 cgttgctgcc gtctgcacac ggtccgcgcg tcgctggaag acctgggctg ggccgattgg 720 gtgctgtcgc cacgggaggt gcaagtgacc atgtgcatcg gcgcgtgccc gagccagttc 780 cgggcggcaa acatgcacgc gcagatcaag acgagcctgc accgcctgaa gcccgacacg 840

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900

A-1850-WO-PCT_SL.txt gtgccagcgc cctgctgcgt gcccgccagc tacaatccca tggtgctcat tcaaaagacc gacaccgggg tgtcgctcca gacctatgat gacttgttag ccaaagactg ccactgcata

960 <210> 215 <211> 320 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 215 Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Gly 1 Gly Pro Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

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Ser Pro 210 Gly Gly Asp His Cys 215 A-1850-WO-PCT_SL.txt Cys Cys Arg Pro Leu Gly Pro Gly Arg 220 Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp 225 230 235 240 Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys 245 250 255 Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser 260 265 270 Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro 275 280 285 Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 290 295 300 Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 305 310 315 320

<210> 216 <211> 636 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 216

ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatgccgg 360 aaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 480 cccgtgctga agtccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtaaa 636

<210> 217 <211> 969 <212> DNA <213> Artificial Sequence <220>

Page 209

A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 217

ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt gcaccctgcc cccatcccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtgcgcgcg acggagacca ctgtccgctc 660 gggcccgggc gttgctgccg tctgcacacg gtccgcgcgt cgctggaaga cctgggctgg 720 gccgattggg tgctgtcgcc acgggaggtg caagtgacca tgtgcatcgg cgcgtgcccg 780 agccagttcc gggcggcaaa catgcacgcg cagatcaaga cgagcctgca ccgcctgaag 840 cccgacacgg tgccagcgcc ctgctgcgtg cccgccagct acaatcccat ggtgctcatt 900 caaaagaccg acaccggggt gtcgctccag acctatgatg acttgttagc caaagactgc 960

cactgcata 969 <210> 218 <211> 323 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 218

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Le u 1 5 10 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Se r 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Gl u 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Th r 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu As n

Page 210

65 70 A-1850-WO- -PCT_SL.txt 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205 Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg 210 215 220 Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp 225 230 235 240 Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile 245 250 255 Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile 260 265 270 Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys 275 280 285 Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp 290 295 300 Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys 305 310 315 320

His Cys Ile <210> 219

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A-1850-WO-PCT_SL.txt <211> 211 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 219

Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 145 150 155 160 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

Pro Gly Lys 210 <210> 220 <211> 210

Page 212

A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 220

Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

Pro Gly 210 <210> 221 <211> 957 <212> DNA

Page 213

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 221 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 420 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 480 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccgggt ggagaccact gtccgctcgg gcccgggcgt 660 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 720 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 780 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 840 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 900 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 957 <210> 222 <211> 319 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 222

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 1 5 10 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

50 55 60

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Arg 65 Val Val Ser Val Leu 70 Thr A-1850-WO-PCT_SL.txt Leu Asn Gly 80 Val Leu His Gln Asp Trp 75 Lys Glu Tyr Lys Cys 85 Lys Val Ser Asn Lys 90 Ala Leu Pro Ala Pro 95 Ile Glu Lys Thr Ile 100 Ser Lys Ala Lys Gly Gln 105 Pro Arg Glu Pro 110 Gln Val Tyr Thr Leu 115 Pro Pro Ser Arg Glu 120 Glu Met Thr Lys Asn 125 Gln Val Ser Leu Thr 130 Cys Leu Val Lys Gly 135 Phe Tyr Pro Ser Asp Ile 140 Ala Val Glu Trp 145 Glu Ser Asn Gly Gln 150 Pro Glu Asn Asn Tyr Asp Thr 155 Thr Pro Pro 160 Val Leu Asp Ser Asp 165 Gly Ser Phe Phe Leu 170 Tyr Ser Asp Leu Thr 175 Val Asp Lys Ser Arg 180 Trp Gln Gln Gly Asn Val 185 Phe Ser Cys Ser 190 Val Met His Glu Ala 195 Leu His Asn His Tyr 200 Thr Gln Lys Ser Leu 205 Ser Leu Ser Pro Gly 210 Gly Asp His Cys Pro 215 Leu Gly Pro Gly Arg Cys 220 Cys Arg Leu His 225 Thr Val Arg Ala Ser 230 Leu Glu Asp Leu Gly Trp Ala 235 Asp Trp Val 240 Leu Ser Pro Arg Glu 245 Val Gln Val Thr Met 250 Cys Ile Gly Ala Cys 255 Pro Ser Gln Phe Arg 260 Ala Ala Asn Met His Ala 265 Gln Ile Lys Thr 270 Ser Leu His Arg Leu 275 Lys Pro Asp Thr Val 280 Pro Ala Pro Cys Cys 285 Val Pro Ala Ser Tyr 290 Asn Pro Met Val Leu 295 Ile Gln Lys Thr Asp Thr 300 Gly Val Ser Leu 305 Gln Thr Tyr Asp Asp 310 Leu Leu Ala Lys Asp Cys His 315 Cys Ile

<210> 223 <211> 633 <212> DNA <213> Artificial Sequence

Page 215

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 223 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggaag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 420 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 480 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccgggt aaa 633 <210> 224 <211> 1032 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 224 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctgggc 780 tgggccgatt gggtgctgtc gccacgggag gtgcaagtga ccatgtgcat cggcgcgtgc 840

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A-1850-WO-PCT_SL.txt ccgagccagt tccgggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac tgccactgca ta

900

960

1020

1032 <210> 225 <211> 322 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 225 Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Gly 1 Pro Ser Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190

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A-1850-WO-PCT_SL.txt

His Glu Ala 195 Leu His Asn His Tyr 200 Thr Gln Lys Ser Leu 205 Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 210 215 220 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 225 230 235 240 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 245 250 255 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 260 265 270 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 275 280 285 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr 290 295 300 Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 305 310 315 320

Cys Ile <210> 226 <211> 211 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 226 Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80

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A-1850-WO-PCT_SL.txt

Lys Glu Tyr Lys Cys 85 Lys Val Ser Asn Lys 90 Ala Leu Pro Ala Pro 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 145 150 155 160 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

195 200 205

Pro Gly Lys 210 <210> 227 <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note^'Descriptioi' of Phe Artificial Sequence Synthetic Met polypeptide Leu Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 <400> 227 Gly Pro Ser Val 1 Phe 5 Ile Ser Arg Thr 20 Pro Glu Val Thr Cys Val 25 Val Val Asp Val 30 Ser His Glu Asp Pro Glu 35 Val Lys Phe Asn Trp Tyr 40 Val Asp Gly Val 45 Glu Val His Asn Ala Lys 50 Thr Lys Pro 55 Arg Glu Glu Gln Tyr 60 Asn Ser Thr Tyr Arg Val Val Ser 65 Val Leu 70 Thr Val Leu His Gln Asp 75 Trp Leu Asn Gly 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Page 219 Pro Ala Pro Ile

85 A-1850-WO 90 -PCT_SL.txt 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

Pro Gly 210 <210> 228 <211> 1023 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 228 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660

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cactacacgc agaagagcct A- ctccctgtct 1850-WO-PCT. ccgggtggag SL.txt accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 ata 1023

<210> 229 <211> 319 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 229

Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 165 170 175

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A-1850-WO-PCT_SL.txt

Asp Lys Ser Arg 180 Trp Gln Gln Gly Asn Val 185 Phe Ser Cys Ser 190 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205 Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu 210 215 220 His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val 225 230 235 240 Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro 245 250 255 Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu 260 265 270 His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala 275 280 285 Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser 290 295 300 Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310 315 <210> 230 <211> 633 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 230 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgccggaag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 420 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 480 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600

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A-1850-WO-PCT_SL.txt acgcagaaga gcctctccct gtctccgggt aaa 633 <210> 231 <211> 966 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 231 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccgggag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 420 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 480 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccgggt gcgcgcgacg gagaccactg tccgctcggg 660 cccgggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc 720 gattgggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc 780 cagttccggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc 840 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa 900 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac 960 tgcata 966 <210> 232 <211> 322 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 232 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 1 5 10 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30

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A-1850-WO-PCT_SL.txt

Glu Asp Pro Glu 35 Val Lys Phe Asn 40 Trp Tyr Val Asp Gly 45 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205 Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys 210 215 220 Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala 225 230 235 240 Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly 245 250 255 Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys 260 265 270 Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys 275 280 285 Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr

290 295 300

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A-1850-WO-PCT_SL.txt

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His 305 310 315 320

Cys Ile <210> 233 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 233 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190

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Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 234 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 234

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 235 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 235

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

1 5 10 15

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A-1850-WO-PCT_SL.txt

Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr 30 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285

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A-1850-WO-PCT_SL.txt

Val Pro 290 Ala Pro Cys Cys Val 295 Pro Ala Ser Tyr Asn 300 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 236 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 236 Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175

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A-1850-WO-PCT_SL.txt

Tyr Ser Asp Leu 180 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 237 <211> 1044 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 237

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 tccggaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg cata 1044

<210> 238 <211> 348 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic

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A-1850-WO-PCT_SL.txt polypeptide

<400> 238 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 210 215 220 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly 225 230 235 240 Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val 245 250 255 Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro

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260 A-1850-WO 265 -PCT_SL.txt 270 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 275 280 285 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 290 295 300 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 305 310 315 320 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 325 330 335 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 340 345

<210> 239 <211> 996 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 239 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg aggtggtgga 660 gcgcgcaacg gagaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

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A-1850-WO-PCT_SL.txt <210> 240 <211> 332 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 240 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu 5 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Thr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Arg Asn Gly 210 215 220

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Asp 225 His Cys Pro Leu Gly 230 Pro A-1850-WO-PCT_SL.txt His Thr Val 240 Gly Arg Cys Cys Arg 235 Leu Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro 245 250 255 Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe 260 265 270 Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu 275 280 285 Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn 290 295 300 Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr 305 310 315 320 Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 325 330

<210> 241 <211> 2145 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 241 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900

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A-1850-WO-PCT_SL.txt

gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cgccgctcag gctgcacagc aagcagccca agcagctcag 1800 cagggaagcg cgcgcgacgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 1860 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 1920 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccgggc ggcaaacatg 1980 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 2040 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 2100 ctccagacct atgatgactt gttagccaaa gactgccact gcata 2145

<210> 242 <211> 715 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 242

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu 1 5 10 15 Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30 Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 40 45 Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys

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A-1850-WO-PCT_SL.txt

50 55 60

Ser 65 Leu His Thr Leu Phe 70 Gly Asp Lys Leu Cys 75 Thr Val Ala Thr Leu 80 Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 90 95 Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu 100 105 110 Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His 115 120 125 Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg 130 135 140 Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg 145 150 155 160 Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala 165 170 175 Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser 180 185 190 Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu 195 200 205 Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro 210 215 220 Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys 225 230 235 240 Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp 245 250 255 Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser 260 265 270 Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His 275 280 285 Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser 290 295 300 Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala 305 310 315 320 Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

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325 A-1850-WO- 330 -PCT_SL.txt 335 Arg His Pro Asp 340 Tyr Ser Val Val Leu Leu 345 Leu Arg Leu Ala 350 Lys Thr Tyr Glu Thr Thr 355 Leu Glu Lys Cys Cys Ala 360 Ala Ala Asp Pro 365 His Glu Cys Tyr Ala Lys 370 Val Phe Asp Glu Phe Lys 375 Pro Leu Val Glu 380 Glu Pro Gln Asn Leu Ile 385 Lys Gln Asn Cys Glu Leu 390 Phe Glu Gln Leu 395 Gly Glu 400 Tyr Lys Phe Gln Asn 405 Ala Leu Leu Val Arg 410 Tyr Thr Lys Lys Val Pro 415 Gln Val Ser Thr 420 Pro Thr Leu Val Glu Val 425 Ser Arg Asn Leu 430 Gly Lys Val Gly Ser Lys 435 Cys Cys Lys His Pro Glu 440 Ala Lys Arg Met 445 Pro Cys Ala Glu Asp Tyr 450 Leu Ser Val Val Leu Asn 455 Gln Leu Cys Val 460 Leu His Glu Lys Thr Pro 465 Val Ser Asp Arg Val Thr 470 Lys Cys Cys Thr 475 Glu Ser 480 Leu Val Asn Arg Arg 485 Pro Cys Phe Ser Ala 490 Leu Glu Val Asp Glu Thr 495 Tyr Val Pro Lys 500 Glu Phe Asn Ala Glu Thr 505 Phe Thr Phe His 510 Ala Asp Ile Cys Thr Leu 515 Ser Glu Lys Glu Arg Gln 520 Ile Lys Lys Gln 525 Thr Ala Leu Val Glu Leu 530 Val Lys His Lys Pro Lys 535 Ala Thr Lys Glu 540 Gln Leu Lys Ala Val Met 545 Asp Asp Phe Ala Ala Phe 550 Val Glu Lys Cys 555 Cys Lys 560 Ala Asp Asp Lys Glu 565 Thr Cys Phe Ala Glu 570 Glu Gly Lys Lys Leu Val 575 Ala Ala Ser Gln 580 Ala Ala Leu Gly Leu Gly 585 Ser Ala Ala Gln 590 Ala Ala Gln Gln Ala Ala Gln Ala Ala Gln Gln Gly Ser Ala Arg Asp Page 236 Gly Asp

A-1850-WO-PCT_SL.txt 595 600 605

His Cys 610 Pro Leu Gly Pro Gly 615 Arg Cys Cys Arg Leu 620 His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg 625 630 635 640 Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg 645 650 655 Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys 660 665 670 Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro 675 680 685 Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr 690 695 700 Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile 705 710 715

<210> 243 <211> 339 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 243 Met Glu Trp Ser 1 Trp Val 5 Phe Leu Phe Phe 10 Leu Ser Val Thr Thr 15 Gly Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110

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A-1850-WO-PCT_SL.txt

Pro Ala Pro Ile Glu 115 Lys Thr Ile 120 Ser Lys Ala Lys Gly 125 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg 225 230 235 240 Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp 245 250 255 Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile 260 265 270 Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile 275 280 285 Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys 290 295 300 Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp 305 310 315 320 Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys 325 330 335

His Cys Ile <210> 244 <211> 1017 <212> DNA <213> Artificial Sequence <220>

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A-1850-WO-PCT_SL.txt <221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 244

atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt ggagaccact gtccgctcgg gcccgggcgt 720 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 780 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 840 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 900 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 960 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 1017

<210> 245 <211> 231 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 245

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly 1 5 10 15 Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

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A-1850-WO-PCT_SL.txt

Asn Ser Thr Tyr Arg 85 Val Val Ser Val Leu 90 Thr Val Leu His Gln 95 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Lys

225 230 <210> 246 <211> 693 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 246 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggaag 420

Page 240 gagatgacca atcgccgtgg gtgctgaagt tggcagcagg acgcagaaga

A-1850-WO-PCT_SL.txt agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480 agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 540 ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 600 ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 gcctctccct gtctccgggt aaa 693

<210> 247 <211> 342 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 247

Met 1 Glu Trp Ser Trp Val 5 Phe Leu Phe Phe 10 Leu Ser Val Thr Thr 15 Gly Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190

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A-1850-WO-PCT_SL.txt

Asp Leu Thr 195 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly 225 230 235 240 Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp 245 250 255 Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr 260 265 270 Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His 275 280 285 Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro 290 295 300 Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln 305 310 315 320 Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala 325 330 335 Lys Asp Cys His Cys Ile

340 <210> 248 <211> 1026 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 248 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480

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A-1850-WO-PCT_SL.txt atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt gcgcgcgacg gagaccactg tccgctcggg 720 cccgggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc 780 gattgggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc 840 cagttccggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc 900 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa 960 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac 1020 tgcata 1026 <210> 249 <211> 339 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 249 Met Glu Trp Ser 1 Trp Val 5 Phe Leu Phe Phe 10 Leu Ser Val Thr Thr 15 Gly Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140

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A-1850-WO-PCT_SL.txt

Asn 145 Gln Val Ser Leu Thr Cys 150 Leu Val Lys Gly Phe Tyr 155 Pro Ser Asp 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg 225 230 235 240 Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp 245 250 255 Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile 260 265 270 Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile 275 280 285 Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys 290 295 300 Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp 305 310 315 320 Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys 325 330 335

His Cys Ile <210> 250 <211> 1017 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 250 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc

120

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cctgaggtca catgcgtggt A- ggtggacgtg 1850-WO-PCT agccacgaag SL.txt accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccgggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt ggagaccact gtccgctcgg gcccgggcgt 720 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 780 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 840 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 900 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 960 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 1017

<210> 251 <211> 231 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 251

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly 1 5 10 15

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

100 105 110

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A-1850-WO-PCT_SL.txt

Pro Ala Pro Ile Glu Lys Thr Ile 120 Ser Lys Ala Lys Gly 125 Gln Pro Arg 115 Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 165 170 175 Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220 Leu Ser Leu Ser Pro Gly Lys

225 230 <210> 252 <211> 693 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 252 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgccggaag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 540 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt aaa 693

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A-1850-WO-PCT_SL.txt <210> 253 <211> 342 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 253 Leu Phe Phe 10 Leu Ser Val Thr Thr 15 Gly Met 1 Glu Trp Ser Trp Val 5 Phe Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 25 30 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 40 45 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 55 60 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 75 80 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 90 95 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 100 105 110 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 115 120 125 Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 130 135 140 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 145 150 155 160 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp 165 170 175 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 180 185 190 Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 195 200 205 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 210 215 220

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A-1850-WO-PCT_SL.txt

Leu 225 Ser Leu Ser Pro Gly Ala 230 Arg Asp Gly Asp 235 His Cys Pro Leu Gly 240 Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp 245 250 255 Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr 260 265 270 Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His 275 280 285 Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro 290 295 300 Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln 305 310 315 320 Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala 325 330 335 Lys Asp Cys His Cys Ile

340 <210> 254 <211> 1026 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 254 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccgggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 480 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccgggt gcgcgcgacg gagaccactg tccgctcggg 720

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A-1850-WO-PCT_SL.txt

cccgggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc 780 gattgggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc 840 cagttccggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc 900 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa 960 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac 1020 tgcata 1026

<210> 255 <211> 341 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 255 Met 1 Asp Met Arg Val 5 Pro Ala Gln Leu Leu 10 Gly Leu Leu Leu Leu 15 Trp Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 165 170 175

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Tyr Asp Thr Thr 180 Pro Pro Val A-1850-WO-PCT_SL.txt Leu Asp Ser Asp Gly Ser 185 Phe 190 Phe Leu Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 210 215 220 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 225 230 235 240 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 245 250 255 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 260 265 270 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 275 280 285 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 290 295 300 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 305 310 315 320 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 325 330 335 Asp Cys His Cys Ile

340 <210> 256 <211> 1023 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 256 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420

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A-1850-WO-PCT_SL.txt cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtggag accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 ata 1023 <210> 257 <211> 233 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 257 Met Asp Met 1 Arg Val 5 Pro Ala Gln Leu Leu 10 Gly Leu Leu Leu Leu 15 Trp Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Page 251

A-1850-WO-PCT_SL.txt

130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 165 170 175 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 180 185 190 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 210 215 220 Lys Ser Leu Ser Leu Ser Pro Gly Lys 225 230

<210> 258 <211> 699 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 258 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cggaaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 540 cctcccgtgc tgaagtccga cggctccttc ttcctctata gcaagctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtaaa 699 <210> 259 <211> 344 <212> PRT <213> Artificial Sequence

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A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 259

Met 1 Asp Met Arg Val 5 Pro Ala Gln Leu Leu 10 Gly Leu Leu Leu Leu 15 Trp Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 165 170 175 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 180 185 190 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 210 215 220 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 225 230 235 240 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 245 250 255

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A-1850-WO-PCT_SL.txt

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu 270 Val Gln 260 265 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 275 280 285 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 290 295 300 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 305 310 315 320 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 325 330 335 Leu Ala Lys Asp Cys His Cys Ile

340 <210> 260 <211> 1032 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 260 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctgggc 780 tgggccgatt gggtgctgtc gccacgggag gtgcaagtga ccatgtgcat cggcgcgtgc 840 ccgagccagt tccgggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 900 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 960

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A-1850-WO-PCT_SL.txt attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac tgccactgca ta

1020

1032 <210> 261 <211> 341 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 261 Met Asp 1 Met Arg Val 5 Pro Ala Gln Leu Leu 10 Gly Leu Leu Leu Leu 15 Trp Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 165 170 175 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 180 185 190 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205

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A-1850-WO-PCT_SL.txt

Phe Ser Cys Ser Val Met His 215 Glu Ala Leu His Asn His Tyr Thr Gln 220 210 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 225 230 235 240 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 245 250 255 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 260 265 270 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 275 280 285 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 290 295 300 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 305 310 315 320 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 325 330 335 Asp Cys His Cys Ile

340 <210> 262 <211> 1023 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 262 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600

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agcaggtggc agcaggggaa A- cgtcttctca 1850-WO-PCT tgctccgtga SL.txt tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtggag accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 ata 1023

<210> 263 <211> 233 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 263 Val 5 Pro Ala Gln Leu Leu 10 Gly Leu Leu Leu Leu 15 Trp Met 1 Asp Met Arg Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160

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A-1850-WO-PCT_SL.txt

Ser Asp Ile Ala Val 165 Glu Trp Glu Ser Asn Gly Gln 170 Pro Glu Asn 175 Asn Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 180 185 190 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 210 215 220 Lys Ser Leu Ser Leu Ser Pro Gly Lys 225 230

<210> 264 <211> 699 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 264 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatgc 420 cggaaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 540 cctcccgtgc tgaagtccga cggctccttc ttcctctata gcaagctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtaaa 699 <210> 265 <211> 344 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 265

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

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1 5 A-1850-WO 10 -PCT_SL.txt 15 Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 25 30 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 40 45 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 55 60 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 75 80 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 90 95 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 100 105 110 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 115 120 125 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 130 135 140 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 145 150 155 160 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 165 170 175 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 180 185 190 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 195 200 205 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 210 215 220 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 225 230 235 240 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 245 250 255 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 260 265 270 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Page 259

A-1850-WO-PCT_SL.txt

275 280 285 Met His 290 Ala Gln Ile Lys Thr 295 Ser Leu His Arg Leu 300 Lys Pro Asp Thr Val 305 Pro Ala Pro Cys Cys 310 Val Pro Ala Ser Tyr 315 Asn Pro Met Val Leu 320 Ile Gln Lys Thr Asp 325 Thr Gly Val Ser Leu 330 Gln Thr Tyr Asp Asp 335 Leu Leu Ala Lys Asp 340 Cys His Cys Ile

<210> 266 <211> 1032 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 266

atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctgggc 780 tgggccgatt gggtgctgtc gccacgggag gtgcaagtga ccatgtgcat cggcgcgtgc 840 ccgagccagt tccgggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 900 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 960 attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 1020 tgccactgca ta 1032

<210> 267

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A-1850-WO-PCT_SL.txt <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 267

Ala 1 Pro Glu Leu Leu Gly Gly Pro Ser 5 Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215

<210> 268 <211> 216

Page 261

A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 268

Ala 1 Pro Glu Leu Leu Gly Gly Pro Ser 5 Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 269 <211> 325 <212> PRT

Page 262

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 269 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Leu Leu Gly 5 Gly Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240

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Gly Trp Ala Asp Trp 245 Val Leu A-1850-WO-PCT_SL.txt Val Thr 255 Met Ser Pro Arg Glu Val 250 Gln Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320 Asp Cys His Cys Ile

325 <210> 270 <211> 975 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 270

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

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A-1850-WO-PCT_SL.txt <210> 271 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 271 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a

120

180

240

300

360

420

480

540

600

651 <210> 272 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 272

Ala Pro 1 Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

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A-1850-WO-PCT_SL.txt

85 90 95

Ala Leu Pro Ala 100 Pro Ile Glu Lys Thr 105 Ile Ser Lys Ala Lys 110 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

<210> 273 <211> 984 <212> DNA <213> Artificial Sequence

325

Page 266

A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 273

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 274 <211> 217 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 274

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu

50 55 60

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A-1850-WO-PCT_SL.txt

Gln 65 Tyr Gly Ser Thr Tyr Arg Val 70 Val Ser Val 75 Cys Thr Val Leu His 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215 <210> 275 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source

<223> /note=Description polypeptide of Gly Artificial Sequence: Synthetic Lys Pro Ser Val 10 Phe Leu Phe Pro Pro 15 <400> 275 Ala Pro Glu 1 Leu Leu Gly 5 Pro Lys Asp Thr 20 Leu Met Ile Ser Arg Thr 25 Pro Glu Val Thr Cys 30 Val Val Val Asp 35 Val Ser His Glu Asp Pro Glu 40 Val Lys Phe 45 Asn Trp Tyr Val Asp Gly 50 Val Glu Val His 55 Asn Cys Lys Thr Lys 60 Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Page 268 Thr Val Leu His

A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 276 <211> 325 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 276 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala Pro 1 Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80

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A-1850-WO-PCT_SL.txt

Gln Asp Trp Leu Asn 85 Gly Lys Glu Tyr Lys 90 Cys Lys Val Ser Asn 95 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro 210 215 220 Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu 225 230 235 240 Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met 245 250 255 Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265 270 Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala 275 280 285 Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300 Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys 305 310 315 320 Asp Cys His Cys Ile

<210> 277 <211> 975

325

Page 270

A-1850-WO-PCT_SL.txt <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 277

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 278 <211> 651 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide <400> 278 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420

Page 271

A-1850-WO-PCT_SL.txt ggcttctatc ccagcgatat tgctgtggaa tgggagtcaa atggccagcc cgagaataac tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg accgtggaca agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a

480

540

600

651 <210> 279 <211> 328 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 279 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190

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A-1850-WO-PCT_SL.txt

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro 210 215 220 Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu 225 230 235 240 Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln 245 250 255 Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn 260 265 270 Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr 275 280 285 Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu 290 295 300 Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu 305 310 315 320 Leu Ala Lys Asp Cys His Cys Ile

325 <210> 280 <211> 984 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polynucleotide

<400> 280 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600

Page 273

gctctgcaca A-1850-WO-PCT_SL.txt 660 accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 281 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 281

Ala Pro 1 Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 115 120 125 Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175

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A-1850-WO-PCT_SL.txt

Val Ser Lys Leu 180 Thr Val Asp Lys Ser 185 Arg Trp Gln Gln Gly 190 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 282 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 282 Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175

Page 275

A-1850-WO-PCT_SL.txt

Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 283 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 283 Ala 1 Pro Glu Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175

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A-1850-WO-PCT_SL.txt

Tyr Ser Lys Leu 180 Thr Val Asp Lys Ser Arg Trp Gln 185 Gln Gly 190 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 284 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 284 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Page 277

A-1850-WO-PCT_SL.txt

180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly 210 215

<210> 285 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 285 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190

Page 278

A-1850-WO-PCT_SL.txt

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 286 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 286 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190

Page 279

A-1850-WO-PCT_SL.txt

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 287 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 287 Ala 1 Pro Glu Leu Leu Gly Gly 5 Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190

Page 280

A-1850-WO-PCT_SL.txt

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 288 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 288 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Page 281

A-1850-WO-PCT_SL.txt 195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 289 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 289 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

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A-1850-WO-PCT_SL.txt

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 290 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 290 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Page 283

A-1850-WO-PCT_SL.txt

Lys Ser Leu Ser Leu Ser Pro Gly 210 215 <210> 291 <211> 216 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 291 Leu Leu 5 Gly Gly Pro Ser Val 10 Phe Leu Phe Pro Pro 15 Lys Ala 1 Pro Glu Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu 165 170 175 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205

Page 284

A-1850-WO-PCT_SL.txt Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 292 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 292 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly

Page 285

A-1850-WO-PCT_SL.txt <210> 293 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 293 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly

Page 286

A-1850-WO-PCT_SL.txt <210> 294 <211> 226 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 294 Leu Leu 15 Gly Asp 1 Lys Thr His Thr Cys 5 Pro Pro Cys Pro Ala 10 Pro Glu Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220

Page 287

A-1850-WO-PCT_SL.txt

Pro Gly

225 <210> 295 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 295 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Page 288

A-1850-WO-PCT_SL.txt

Gly <210> 296 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 296 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly

Page 289

A-1850-WO-PCT_SL.txt <210> 297 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 297 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly

Page 290

A-1850-WO-PCT_SL.txt <210> 298 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 298 Asp Thr Leu Met 15 Ile Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly

Page 291

A-1850-WO-PCT_SL.txt <210> 299 <211> 211 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 299

Gly 1 Gly Pro Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 145 150 155 160 Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

Ser Pro Gly

210

Page 292

A-1850-WO-PCT_SL.txt <210> 300 <211> 211 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 300

Gly 1 Gly Pro Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 145 150 155 160 Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

<210> 301

Ser Pro Gly

210

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A-1850-WO-PCT_SL.txt <211> 210 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 301

Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 145 150 155 160 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

<210> 302 <211> 210

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Pro Gly

210

A-1850-WO-PCT_SL.txt <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 302

Gly 1 Pro Ser Val Phe 5 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 145 150 155 160 Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

<210> 303 <211> 212 <212> PRT

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Pro Gly

210

A-1850-WO-PCT_SL.txt <213> Artificial Sequence <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 303

Gly 1 Gly Pro Ser Val 5 Phe Leu Phe Pro Pro 10 Lys Pro Lys Asp Thr 15 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 25 30 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 40 45 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 55 60 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 75 80 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 90 95 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105 110 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 115 120 125 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 130 135 140 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 145 150 155 160 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 165 170 175 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185 190 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200 205

<210> 304 <211> 211 <212> PRT <213> Artificial Sequence

Ser Pro Gly Lys

210

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A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide

<400> 304 Leu Phe Pro Pro Lys 10 Pro Lys Asp Thr Leu 15 Met Gly 1 Pro Ser Val Phe 5 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 25 30 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 40 45 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 55 60 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 75 80 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 90 95 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 100 105 110 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 115 120 125 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 130 135 140 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 145 150 155 160 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 165 170 175 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 180 185 190 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 195 200 205

<210> 305 <211> 210 <212> PRT <213> Artificial Sequence

Pro Gly Lys

210

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A-1850-WO-PCT_SL.txt <220>

<221> source <223> /note=Description of Artificial Sequence: Synthetic polypeptide <400> 305

Pro 1 Ser Val Phe Leu 5 Phe Pro Pro Lys Pro 10 Lys Asp Thr Leu Met 15 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 100 105 110 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 115 120 125 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 130 135 140 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 145 150 155 160 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 165 170 175 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 180 185 190 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Lys

210

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